Substituted heterocyclic compounds and methods of use

ABSTRACT

The present invention relates to pyrimidinones and pyridones and derivatives thereof, and pharmaceutically acceptable salts thereof. Also included is a method of treatment of inflammation, rheumatoid arthritis, Pagets disease, osteoporosis, multiple myeloma, uveititis, acute or chronic myelogenous leukemia, pancreatic β cell destruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn&#39;s disease, allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, Reiter&#39;s syndrome, type I diabetes, type II diabetes, bone resorption diseases, graft vs. host reaction, Alzheimer&#39;s disease, stroke, myocardial infarction, ischemia reperfusion injury, atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses or herpes zoster infection in a mammal comprising administering an effective amount a compound as described above.

This application claims the benefit of U.S. Provisional Application No.60/538,948, filed Jan. 22, 2004, which is hereby incorporated byreference.

BACKGROUND OF THE INVENTION

The present invention comprises a new class of compounds useful intreating diseases, such as TNF-α, IL-1β, IL-6 and/or IL-8 mediateddiseases and other maladies, such as pain and diabetes. In particular,the compounds of the invention are useful for the prophylaxis andtreatment of diseases or conditions involving inflammation. Thisinvention also relates to intermediates and processes useful in thepreparation of such compounds.

Interleukin-1 (IL-1) and Tumor Necrosis Factor α (TNF-α) arepro-inflammatory cytokines secreted by a variety of cells, includingmonocytes and macrophages, in response to many inflammatory stimuli(e.g., lipopolysaccharide-LPS) or external cellular stress (e.g.,osmotic shock and peroxide).

Elevated levels of TNF-α and/or IL-1 over basal levels have beenimplicated in mediating or exacerbating a number of disease statesincluding rheumatoid arthritis; Pagets disease; osteoporosis; multiplemyeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic βcell destruction; osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease; adult respiratory distresssyndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis;ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscledegeneration; cachexia; Reiter's syndrome; type I and type II diabetes;bone resorption diseases; graft vs. host reaction; ischemia reperfusioninjury; atherosclerosis; brain trauma; multiple sclerosis; cerebralmalaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgiasdue to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza,adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpeszoster are also exacerbated by TNF-α.

It has been reported that TNF-α plays a role in head trauma, stroke, andischemia. For instance, in animal models of head trauma (rat), TNF-αlevels increased in the contused hemisphere (Shohami et al., J. Cereb.Blood Flow Metab. 14, 615 (1994)). In a rat model of ischemia whereinthe middle cerebral artery was occluded, the levels of TNF-α mRNA ofTNF-α increased (Feurstein et al., Neurosci. Lett. 164, 125 (1993)).Administration of TNF-α into the rat cortex has been reported to resultin significant neutrophil accumulation in capillaries and adherence insmall blood vessels. TNF-α promotes the infiltration of other cytokines(IL-1, IL-6) and also chemokines, which promote neutrophil infiltrationinto the infarct area (Feurstein, Stroke 25, 1481 (1994)). TNF-α hasalso been implicated to play a role in type II diabetes (Endocrinol.130, 43-52, 1994; and Endocrinol. 136, 1474-1481, 1995).

TNF-α appears to play a role in promoting certain viral life cycles anddisease states associated with them. For instance, TNF-α secreted bymonocytes induced elevated levels of HIV expression in a chronicallyinfected T cell clone (Clouse et al., J. Immunol. 142, 431 (1989)).Lahdevirta et al., (Am. J. Med. 85, 289 (1988)) discussed the role ofTNF-α in the HIV associated states of cachexia and muscle degradation.

TNF-α is upstream in the cytokine cascade of inflammation. As a result,elevated levels of TNF-α may lead to elevated levels of otherinflammatory and proinflammatory cytokines, such as IL-1, IL-6, andIL-8.

Elevated levels of IL-1 over basal levels have been implicated inmediating or exacerbating a number of disease states includingrheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease; adult respiratory distresssyndrome (ARDS); psoriasis; Crohn's disease; ulcerative colitis;anaphylaxis; muscle degeneration; cachexia; Reiter's syndrome; type Iand type II diabetes; bone resorption diseases; ischemia reperfusioninjury; atherosclerosis; brain trauma; multiple sclerosis; sepsis;septic shock; and toxic shock syndrome. Viruses sensitive to TNF-αinhibition, e.g., HIV-1, HIV-2, HIV-3, are also affected by IL-1.

TNF-α and IL-1 appear to play a role in pancreatic β cell destructionand diabetes. Pancreatic β cells produce insulin which helps mediateblood glucose homeostasis. Deterioration of pancreatic β cells oftenaccompanies type I diabetes. Pancreatic β cell functional abnormalitiesmay occur in patients with type II diabetes. Type II diabetes ischaracterized by a functional resistance to insulin. Further, type IIdiabetes is also often accompanied by elevated levels of plasma glucagonand increased rates of hepatic glucose production. Glucagon is aregulatory hormone that attenuates liver gluconeogenesis inhibition byinsulin. Glucagon receptors have been found in the liver, kidney andadipose tissue. Thus glucagon antagonists are useful for attenuatingplasma glucose levels (WO 97/16442, incorporated herein by reference inits entirety). By antagonizing the glucagon receptors, it is thoughtthat insulin responsiveness in the liver will improve, therebydecreasing gluconeogenesis and lowering the rate of hepatic glucoseproduction.

In rheumatoid arthritis models in animals, multiple intra-articularinjections of IL-1 have led to an acute and destructive form ofarthritis (Chandrasekhar et al., Clinical Immunol Immunopathol. 55, 382(1990)). In studies using cultured rheumatoid synovial cells, IL-1 is amore potent inducer of stromelysin than is TNF-α (Firestein, Am. J.Pathol. 140, 1309 (1992)). At sites of local injection, neutrophil,lymphocyte, and monocyte emigration has been observed. The emigration isattributed to the induction of chemokines (e.g., IL-8), and theup-regulation of adhesion molecules (Dinarello, Eur. Cytokine Netw. 5,517-531 (1994)).

IL-1 also appears to play a role in promoting certain viral life cycles.For example, cytokine-induced increase of HIV expression in achronically infected macrophage line has been associated with aconcomitant and selective increase in IL-1 production (Folks et al., J.Immunol. 136, 40 (1986)). Beutler et al. (J. Immunol. 135, 3969 (1985))discussed the role of IL-1 in cachexia. Baracos et al. (New Eng. J. Med.308, 553 (1983)) discussed the role of IL-1 in muscle degeneration.

In rheumatoid arthritis, both IL-1 and TNF-α induce synoviocytes andchondrocytes to produce collagenase and neutral proteases, which leadsto tissue destruction within the arthritic joints. In a model ofarthritis (collagen-induced arthritis (CIA) in rats and mice),intra-articular administration of TNF-α either prior to or after theinduction of CIA led to an accelerated onset of arthritis and a moresevere course of the disease (Brahn et al., Lymphokine Cytokine Res. 11,253 (1992); and Cooper, Clin. Exp. Immunol. 898, 244 (1992)).

IL-8 has been implicated in exacerbating and/or causing many diseasestates in which massive neutrophil infiltration into sites ofinflammation or injury (e.g., ischemia) is mediated by the chemotacticnature of IL-8, including, but not limited to, the following: asthma,inflammatory bowel disease, psoriasis, adult respiratory distresssyndrome, cardiac and renal reperfusion injury, thrombosis andglomerulonephritis. In addition to the chemotaxis effect on neutrophils,IL-8 also has the ability to activate neutrophils. Thus, reduction inIL-8 levels may lead to diminished neutrophil infiltration.

Several approaches have been taken to block the effect of TNF-α:. Oneapproach involves using soluble receptors for TNF-α (e.g., TNFR-55 orTNFR-75), which have demonstrated efficacy in animal models ofTNF-α-mediated disease states. A second approach to neutralizing TNF-αusing a monoclonal antibody specific to TNF-α, cA2, has demonstratedimprovement in swollen joint count in a Phase II human trial ofrheumatoid arthritis (Feldmann et al., Immunological Reviews, pp.195-223 (1995)). These approaches block the effects of TNF-α and IL-1 byeither protein sequestration or receptor antagonism.

U.S. Pat. No. 5,100,897, incorporated herein by reference in itsentirety, describes pyrimidinone compounds useful as angiotensin IIantagonists wherein one of the pyrimidinone ring nitrogen atoms issubstituted with a substituted phenylmethyl or phenethyl radical.

U.S. Pat. No. 5,162,325, incorporated herein by reference in itsentirety, describes pyrimidinone compounds useful as angiotensin IIantagonists wherein one of the pyrimidinone ring nitrogen atoms issubstituted with a substituted phenylmethyl radical.

EP 481448, incorporated herein by reference in its entirety, describespyrimidinone compounds useful as angiotensin II antagonists wherein oneof the pyrimidinone ring nitrogen atoms is substituted with asubstituted phenyl, phenylmethyl or phenethyl radical.

CA 2,020,370, incorporated herein by reference in its entirety,describes pyrimidinone compounds useful as angiotensin II antagonistswherein one of the pyrimidinone ring nitrogen atoms is substituted witha substituted biphenylaliphatic hydrocarbon radical.

BRIEF DESCRIPTION OF THE INVENTION

The present invention comprises a new class of compounds useful in theprophylaxis and treatment of diseases, such as TNF-α, IL-1β, IL-6 and/orIL-8 mediated diseases and other maladies, such as pain and diabetes. Inparticular, the compounds of the invention are useful for theprophylaxis and treatment of diseases or conditions involvinginflammation. Accordingly, the invention also comprises pharmaceuticalcompositions comprising the compounds; methods for the prophylaxis andtreatment of TNF-α, IL-1β, IL-6 and/or IL-8 mediated diseases, such asinflammatory, pain and diabetes diseases, using the compounds andcompositions of the invention, and intermediates and processes usefulfor the preparation of the compounds of the invention.

The compounds of the invention are represented by the following generalstructure:

wherein R¹, R², R³, R⁴, R⁵, R⁶, J and X are defined herein.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents and other publications recited herein are herebyincorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided compounds ofthe formula:

or a pharmaceutically acceptable salt or hydrate thereof, wherein

-   -   J is ═O, ═S, ═CHNO₂, ═N—CN, ═CHSO₂R^(b), ═NSO₂R^(b) or ═NHR^(b);    -   X is, independently at each instance, N or CR³;    -   R¹ is a saturated or unsaturated 5- or 6-membered, ring        containing 0, 1, 2 or 3 atoms selected from N, O and S, wherein        the ring is substituted by 0, 1, 2 or 3 substituents selected        from C₁₋₄alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),        —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),        S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆        alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);    -   R² is C₁₋₈alkyl substituted by 0, 1, 2 or 3 substituents        selected from C₁₋₂haloalkyl, halo, oxo, cyano, nitro,        —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),        —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),        —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆        alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a), and additionally        substituted by 0, 1 or 2 substituents selected from R^(g),        —C(═O)R^(g), —C(═O)OR^(g), —C(═O)NR^(a)R^(g),        —C(═NR^(a))NR^(a)R^(g), —OR^(g), —OC(═O)R^(g),        —OC(═O)NR^(a)R^(g), —OC(═O)N(R^(a))S(═O)₂R^(g),        —OC₂₋₆alkylNR^(a)R^(g), —OC₂₋₆alkylOR^(g), —SR^(g), —S(═O)R^(g),        —S(═O)₂R^(g), —S(═O)₂NR^(a)R^(g), —NR^(a)R^(g),        —N(R^(a))C(═O)R^(g), —N(R^(a))C(═O)OR^(g),        —N(R^(a))C(═O)NR^(a)R^(g), —C(═O)R^(e), C(═O)OR^(e),        —C(═O)NR^(a)R^(e), —C(═NR^(a))NR^(a)R^(e), —OR^(e),        —OC(═O)R^(e), —OC(═O)NR^(a)R^(e), —OC(═O)N(R^(a))S(═O)₂R^(e),        —OC₂₋₆alkyNR^(a)R^(e), —OC₂₋₆alkylOR^(e), —SR^(e), —S(═O)R^(e),        —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(e), —NR^(a)R^(e),        —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(e) and        —N(R^(a))C(═O)NR^(a)R^(e);    -   R³ is selected from H, R^(e), C₁₋₄haloalkyl, halo, cyano, nitro,        —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),        —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),        —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a);    -   R⁶ is independently at each instance H, R^(d), R^(e) or R^(g);    -   R⁷ is independently at each instance H, R^(d), R^(e) or R^(g);    -   m is 2 or 3;    -   R^(a) is independently, at each instance, H or R^(b);    -   R^(b) is independently, at each instance, phenyl, benzyl or        C₁₋₆alkyl, the phenyl, benzyl and C₁₋₆alkyl being substituted by        0, 1, 2 or 3 substituents selected from halo, C₁₋₄alkyl,        C₁₋₃haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl,        —N(C₁₋₄alkyl)C₁₋₄alkyl;    -   R^(d) is independently at each instance C₁₋₈alkyl,        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),        —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),        —OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a);    -   R^(e) is independently at each instance C₁₋₆alkyl substituted by        0, 1, 2 or 3 substituents independently selected from R^(d) and        additionally substituted by 0 or 1 substituents selected from        R^(g) ; and    -   R^(g) is independently at each instance a saturated, partially        saturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-,        7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2,        3 or 4 atoms selected from N, O and S, wherein the carbon atoms        of the ring are substituted by 0, 1 or 2 oxo groups and the ring        is substituted by 0, 1, 2 or 3 substituents selected from        C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),        —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),        —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with the above and belowembodiments, R¹ is a saturated or unsaturated 5- or 6-membered, ringcontaining 0, 1, 2 or 3 atoms selected from N, O and S, wherein the ringis substituted by 1, 2 or 3 substituents selected from C₁₋₄alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with the above and belowembodiments,

-   -   R^(a) is a saturated or unsaturated 5- or 6-membered, ring        containing 0, 1, 2 or 3 atoms selected from N, O and S, wherein        the ring is substituted by 1, 2 or 3 substituents selected from        C₁₋₄alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —OR^(a),        —OC(═O)R^(b), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —NR^(a)R^(a)        and —N(R^(a))C(═O)R^(b).

In another embodiment, in conjunction with the above and belowembodiments,

-   -   R¹ is a saturated or unsaturated 5- or 6-membered, ring        containing 0, 1, 2 or 3 atoms selected from N, O and S, wherein        the ring is substituted by 0, 1, 2 or 3 substituents selected        from C₁₋₄alkyl, C₁₋₄haloalkyl and halo.

In another embodiment, in conjunction with the above and belowembodiments,

-   -   R¹ is a saturated or unsaturated 6-membered, ring containing 0,        1, 2 or 3 atoms selected from N, O and S, wherein the ring is        substituted by 0, 1, 2 or 3 substituents selected from        C₁₋₄alkyl, C₁₋₄haloalkyl and halo.

In another embodiment, in conjunction with the above and belowembodiments,

-   -   R¹ is phenyl substituted by 0, 1, 2 or 3 substituents selected        from C₁₋₄alkyl, C₁₋₄haloalkyl and halo.

In another embodiment, in conjunction with the above and belowembodiments,

-   -   R¹ is pyridinyl substituted by 0, 1, 2 or 3 substituents        selected from C₁₋₄alkyl, C₁₋₄haloalkyl and halo.

In another embodiment, in conjunction with the above and belowembodiments,

-   -   R¹ is pyrimidinyl substituted by 0, 1, 2 or 3 substituents        selected from C₁₋₄alkyl, C₁₋₄haloalkyl and halo.

In another embodiment, in conjunction with the above and belowembodiments,

-   -   R¹ is a saturated or unsaturated 5-membered, ring containing 1        or 2 atoms selected from N, O and S, wherein the ring is        substituted by 0, 1, 2 or 3 substituents selected from        C₁₋₄alkyl, C₁₋₄haloalkyl and halo.

In another embodiment, in conjunction with the above and belowembodiments,

-   -   R² is C₁₋₈alkyl substituted by 0, 1, 2 or 3 substituents        selected from C₁₋₂haloalkyl, halo, oxo, cyano, nitro,        —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),        —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),        —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆        alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a), and additionally        substituted by 0, 1 or 2 substituents selected from R^(g),        —C(═O)R^(g), —C(═O)OR^(g), —C(═O)NR^(a)R^(g),        —C(═NR^(a))NR^(a)R^(g), —OR^(g), —OC(═O)R^(g),        —OC(═O)NR^(a)R^(g), —OC(═O)N(R^(a))S(═O)₂R^(g),        —OC₂₋₆alkylNR^(a)R^(g), —OC₂₋₆alkylOR^(g), —SR^(g), —S(═O)R^(g),        —S(═O)₂R^(g), —S(═O)₂NR^(a)R^(g), —NR^(a)R^(g),        —N(R^(a))C(═O)R^(g), —N(R^(a))C(═O)OR^(g),        —N(R^(a))C(═O)NR^(a)R^(g), —C(═O)R^(e), —C(═O)OR^(e),        —C(═O)NR^(a)R^(e), —C(═NR^(a))NR^(a)R^(e), —OR^(e),        —OC(═O)R^(e), —OC(═O)NR^(a)R^(e), —OC(═O)N(R^(a))S(═O)₂R^(e),        —OC₂₋₆alkylNR^(a)R^(e), —OC₂₋₆alkylOR^(e), —SR^(e), —S(═O)R^(e),        —S(═)₂R^(e), —S(═O)₂NR^(a)R^(e), —NR^(a)R^(e),        —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(e) and        —N(R^(a))C(═O)NR^(a)R^(e).

In another embodiment, in conjunction with the above and belowembodiments,

-   -   R² is C₁₋₈alkyl substituted by 0, 1, 2 or 3 substituents        selected from C₁₋₂haloalkyl, halo, oxo, cyano, nitro,        —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),        —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),        —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a), and        additionally substituted by R^(g).

In another embodiment, in conjunction with the above and belowembodiments,

-   -   R² is C₁₋₈alkyl substituted by 1, 2 or 3 substituents selected        from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(b),        —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),        —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a), and        additionally substituted by R^(g).

In another embodiment, in conjunction with the above and belowembodiments, R² is C₁₋₈alkyl substituted by R^(g).

In another embodiment, in conjunction with the above and belowembodiments,

-   -   R² is —C₁₋₆alkylphenyl, wherein the phenyl is 0, 1, 2 or 3        substituents selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,        cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),        —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),        —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a)) S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), S(═O)R^(b),        —S(═)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with the above and belowembodiments,

-   -   R³ is selected from R^(e), C₁₋₄haloalkyl, halo, cyano, nitro,        —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),        —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),        —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with the above and belowembodiments, R³is H.

In another embodiment, in conjunction with any of the above and belowembodiments, J is ═O or ═S.

In another embodiment, in conjunction with any of the above and belowembodiments, J is ═CHNO₂ or ═CHSO₂R^(b).

In another embodiment, in conjunction with any of the above and belowembodiments, J is ═N—CN, ═NSO₂R^(b) or ═NR^(b).

Another aspect of the invention relates to compounds having thestructure

or a pharmaceutically acceptable salt or hydrate thereof, wherein

-   -   J is ═O, ═S, ═CHNO₂, ═N—CN, ═CHSO₂R^(b), ═NSO₂R^(b) or ═NHR^(b);    -   X is, independently at each instance, N or CR³;    -   R¹ is a saturated or unsaturated 5-, 6- or 7-membered, ring        containing 0, 1, 2 or 3 atoms selected from N, O and S, wherein        the ring is substituted by 0, 1, 2 or 3 substituents selected        from C₁₋₄alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),        —C(═)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),        —OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR C₂₋₆alkylOR^(a); wherein R¹        is not thiazole, imidazole or pyrazole;    -   R² is C₂₋₈alkyl substituted by 0, 1, 2 or 3 substituents        selected from C₁₋₂haloalkyl, halo, oxo, cyano, nitro,        —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),        —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),        —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a), and        additionally substituted by 0, 1 or 2 substituents selected from        R^(g), —C(═O)R^(g), —C(═O)OR^(g), —C(═O)NR^(a)R^(g),        —C(═NR^(a))NR^(a)R^(g), —OR^(g), —OC(═O)R^(g),        —OC(═O)NR^(a)R^(g), —OC(═O)N(R^(a))S(═O)₂R^(g),        —OC₂₋₆alkylNR^(a)R^(g), —OC₂₋₆alkylOR^(g), —SR^(g), —S(═O)R^(g),        —S(═O)₂R^(g), ═—S(═O)₂NR^(a)R^(g), —NR^(a)R^(g),        —N(R^(a))C(═O)R^(g), —N(R^(a))C(═O)OR^(g),        —N(R^(a))C(═O)NR^(a)R^(g), —C(═O)R^(e), C(═O)OR^(e),        —C(═O)NR^(a)R^(e), —C(═NR^(a))NR^(a)R^(e), —OR^(e),        —OC(═O)R^(e), —OC(═O)NR^(a)R^(e), —OC(═O)N(R^(a))S(═O)₂R^(e),        —OC₂₋₆alkylNR^(a)R^(e), —OC₂₋₆alkylOR^(e), —SR^(e), —S(═O)R^(e),        —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(e), —NR^(a)R^(e),        —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(e) and        —N(R^(a))C(═O)NR^(a)R^(e);    -   R³ is independently, in each instance, selected from H, R^(e),        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),        —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),        —OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a);    -   R⁴ is H, R^(e) or R^(g);    -   R⁵ is H, R^(e) or R^(g) ;    -   R⁶ is independently at each instance H, R^(d) , R^(e) or R^(g) ;    -   R⁷ is independently at each instance H, R^(d) , R^(e) or R^(g) ;    -   R^(a) is independently, at each instance, H or R^(b);    -   R^(b) is independently, at each instance, phenyl, benzyl or        C₁₋₆alkyl, the phenyl, benzyl and C₁₋₆alkyl being substituted by        0, 1, 2 or 3 substituents selected from halo, C₁₋₄alkyl,        C₁₋₃haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl,        —N(C₁₋₄alkyl)C₁₋₄alkyl;    -   R^(d) is independently at each instance C₁₋₈alkyl,        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),        —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),        —OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a);    -   R^(e) is independently at each instance C₁₋₆alkyl substituted by        0, 1, 2 or 3 substituents independently selected from R^(d) and        additionally substituted by 0 or 1 substituents selected from        R^(g) ; and    -   R^(g) is independently at each instance a saturated, partially        saturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-,        7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2,        3 or 4 atoms selected from N, O and S, wherein the carbon atoms        of the ring are substituted by 0, 1 or 2 oxo groups and the ring        is substituted by 0, 1, 2 or 3 substituents selected from        C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),        —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),        —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR        C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with the above and belowembodiments, R¹ is thiophenyl, furanyl, pyrrolyl, oxazole or triazole,any of which is substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₄alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a)) C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R and —NR^(a)C₂₋₆alkylOR^(a); wherein R¹ is not thiazole,imidazole or pyrazole.

In another embodiment, in conjunction with the above and belowembodiments, R¹ is a saturated or unsaturated 6-membered, ringcontaining 1, 2 or 3 atoms selected from N, O and S, wherein the ring issubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₄alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₁₋₆alkylOR^(a).

In another embodiment, in conjunction with the above and belowembodiments, R¹ is an unsaturated 6-membered, ring containing 1, 2 or 3N atoms, wherein the ring is substituted by 0, 1, 2 or 3 substituentsselected from C₁₋₄alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with the above and belowembodiments, R¹ is phenyl substituted by 0, 1, 2 or 3 substituentsselected from C₁₋₄alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with the above and belowembodiments, R¹ is phenyl substituted by 1, 2 or 3 substituents selectedfrom C₁₋₄alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with the above and belowembodiments, R¹ is phenyl, pyridinyl or pyrimidinyl, all of which aresubstituted by 0, 1 or 2 substituents selected from halo, C₁₋₃alkyl andCF₃.

In another embodiment, in conjunction with the above and belowembodiments, R¹ is phenyl, pyridinyl or pyrimidinyl.

In another embodiment, in conjunction with the above and belowembodiments, R¹ is phenyl.

In another embodiment, in conjunction with the above and belowembodiments, R² is C₂₋₈alkyl.

In another embodiment, in conjunction with the above and belowembodiments, R² is C₂₋₈alkyl substituted by R^(g).

In another embodiment, in conjunction with the above and belowembodiments, R² is C₂₋₈alkyl substituted by 1, 2 or 3 substituentsselected from C₁₋₂haloalkyl, halo, oxo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a), and additionallysubstituted by R^(g).

In another embodiment, in conjunction with the above and belowembodiments, R² is C₂₋₈alkyl substituted by phenyl, the phenyl beingsubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with the above and belowembodiments, R² is C₂₋₈alkyl substituted by 1, 2 or 3 substituentsselected from C₁₋₂haloalkyl, halo, oxo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —C(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a), and additionallysubstituted by , the phenyl being substituted by 0, 1, 2 or 3substituents selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with the above and belowembodiments,

-   -   R³ is selected from R^(e), C₁₋₄haloalkyl, halo, cyano, nitro,        —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),        —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),        —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with the above and belowembodiments, R³ is H.

In another embodiment, in conjunction with any of the above and belowembodiments, J is ═O or ═S.

In another embodiment, in conjunction with any of the above and belowembodiments, J is ═CHNO₂ or ═CHSO₂R^(b).

In another embodiment, in conjunction with any of the above and belowembodiments, J is ═N—CN, ═NSO₂R^(b) or ═NR^(b).

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound according to any one of the above embodiments anda pharmaceutically acceptable carrier.

Another aspect of the invention relates to a method of prophylaxis ortreatment of inflammation comprising administering an effective amountof a compound according to any one of the above embodiments.

Another aspect of the invention relates to a method of prophylaxis ortreatment of rheumatoid arthritis, Pagets disease, osteoporosis,multiple myeloma, uveititis, acute or chronic myelogenous leukemia,pancreatic β cell destruction, osteoarthritis, rheumatoid spondylitis,gouty arthritis, inflammatory bowel disease, adult respiratory distresssyndrome (ARDS), psoriasis, Crohn's disease, allergic rhinitis,ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscledegeneration, cachexia, Reiter's syndrome, type I diabetes, type IIdiabetes, bone resorption diseases, graft vs. host reaction, Alzheimer'sdisease, stroke, myocardial infarction, ischemia reperfusion injury,atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria,sepsis, septic shock, toxic shock syndrome, fever, myalgias due toHIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, theherpes viruses or herpes zoster infection in a mammal comprisingadministering an effective amount of a compound according to any one ofthe above embodiments.

Another aspect of the invention relates to a method of lowering plasmaconcentrations of either or both TNF-α and IL-1 comprising administeringan effective amount of a compound according to any one of the aboveembodiments.

Another aspect of the invention relates to a method of lowering plasmaconcentrations of either or both IL-6 and IL-8 comprising administeringan effective amount of a compound according to any one of the aboveembodiments.

Another aspect of the invention relates to a method of prophylaxis ortreatment of diabetes disease in a mammal comprising administering aneffective amount of a compound according to any one of the aboveembodiments to produce a glucagon antagonist effect.

Another aspect of the invention relates to a method of prophylaxis ortreatment of a pain disorder in a mammal comprising administering aneffective amount of a compound according to any one of the aboveembodiments.

Another aspect of the invention relates to a method of decreasingprostaglandins production in a mammal comprising administering aneffective amount of a compound according to any one of the aboveembodiments.

Another aspect of the invention relates to a method of decreasingcyclooxygenase enzyme activity in a mammal comprising administering aneffective amount of a compound according to any one of the aboveembodiments. In another embodiment, the cyclooxygenase enzyme is COX-2.

Another aspect of the invention relates to a method of decreasingcyclooxygenase enzyme activity in a mammal comprising administering aneffective amount of the above pharmaceutical composition. In anotherembodiment the cyclooxygenase enzyme is COX-2.

Another aspect of the invention relates to the manufacture of amedicament comprising a compound according to any one of the aboveembodiments.

Another aspect of the invention relates to the manufacture of amedicament for the treatment of inflammation comprising administering aneffective amount of a compound according to any one of the aboveembodiments.

Another aspect of the invention relates to the manufacture of amedicament for the treatment of rheumatoid arthritis, Pagets disease,osteoporosis, multiple myeloma, uveititis, acute or chronic myelogenousleukemia, pancreatic D cell destruction, osteoarthritis, rheumatoidspondylitis, gouty arthritis, inflammatory bowel disease, adultrespiratory distress syndrome (ARDS), psoriasis, Crohn's disease,allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis,asthma, muscle degeneration, cachexia, Reiter's syndrome, type Idiabetes, type II diabetes, bone resorption diseases, graft vs. hostreaction, Alzheimer's disease, stroke, myocardial infarction, ischemiareperfusion injury, atherosclerosis, brain trauma, multiple sclerosis,cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever,myalgias due to HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza,adenovirus, the herpes viruses or herpes zoster infection in a mammalcomprising administering an effective amount of a compound according toany one of the above embodiments.

The compounds of this invention may have in general several asymmetriccenters and are typically depicted in the form of racemic mixtures. Thisinvention is intended to encompass racemic mixtures, partially racemicmixtures and separate enantiomers and diasteromers.

The specification and claims contain listing of species using thelanguage “selected from . . . and . . .” and “is . . . or . . .”(sometimes referred to as Markush groups). When this language is used inthis application, unless otherwise stated it is meant to include thegroup as a whole, or any single members thereof, or any subgroupsthereof. The use of this language is merely for shorthand purposes andis not meant in any way to limit the removal of individual elements orsubgroups as needed.

Unless otherwise specified, the following definitions apply to termsfound in the specification and claims:

-   -   “Aryl” means a phenyl or naphthyl radical, wherein the phenyl        may be fused with a C₃₋₄cycloalkyl bridge.    -   “Benzo group”, alone or in combination, means the divalent        radical C₄H₄═, one representation of which is —CH═CH—CH═CH—,        that when vicinally attached to another ring forms a        benzene-like ring—for example tetrahydronaphthylene, indole and        the like. “C_(α-μ)alkyl” means an alkyl group comprising from α        to βcarbon atoms in a branched, cyclical or linear relationship        or any combination of the three. The alkyl groups described in        this section may also contain double or triple bonds. Examples        of C₁₋₈alkyl include, but are not limited to the following:        “Halogen” and “halo” mean a halogen atoms selected from F, Cl,        Br and I. “C_(α-β)haloalkyl” means an alkyl group, as described        above, wherein any number—at least one—of the hydrogen atoms        attached to the alkyl chain are replaced by F, Cl, Br or I.        “Heterocycle” means a ring comprising at least one carbon atom        and at least one other atom selected from N, O and S. Examples        of heterocycles that may be found in the claims include, but are        not limited to, the following:

“Pharmaceutically-acceptable salt” means a salt prepared by conventionalmeans, and are well known by those skilled in the art. The“pharmacologically acceptable salts” include basic salts of inorganicand organic acids, including but not limited to hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid,ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaricacid, citric acid, lactic acid, fumaric acid, succinic acid, maleicacid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid andthe like. When compounds of the invention include an acidic functionsuch as a carboxy group, then suitable pharmaceutically acceptablecation pairs for the carboxy group are well known to those skilled inthe art and include alkaline, alkaline earth, ammonium, quaternaryammonium cations and the like. For additional examples of“pharmacologically acceptable salts,” see infra and Berge et al., J.Pharm. Sci. 66:1 (1977). “Leaving group” generally refers to groupsreadily displaceable by a nucleophile, such as an amine, a thiol or analcohol nucleophile. Such leaving groups are well known in the art.Examples of such leaving groups include, but are not limited to,N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates,tosylates and the like. Preferred leaving groups are indicated hereinwhere appropriate. “Protecting group” generally refers to groups wellknown in the art which are used to prevent selected reactive groups,such as carboxy, amino, hydroxy, mercapto and the like, from undergoingundesired reactions, such as nucleophilic, electrophilic, oxidation,reduction and the like. Preferred protecting groups are indicated hereinwhere appropriate. Examples of amino protecting groups include, but arenot limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl andsubstituted cycloalkenyl alkyl, allyl, substituted allyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples ofaralkyl include, but are not limited to, benzyl, ortho-methylbenzyl,trityl and benzhydryl, which can be optionally substituted with halogen,alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts,such as phosphonium and ammonium salts. Examples of aryl groups includephenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl),phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl orsubstituted cycloalkylenylalkyl radicals, preferably have 6-10 carbonatoms, include, but are not limited to, cyclohexenyl methyl and thelike. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups includebenzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl,substituted benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloroacetyl, phthaloyl and the like. A mixture of protecting groups can beused to protect the same amino group, such as a primary amino group canbe protected by both an aralkyl group and an aralkoxycarbonyl group.Amino protecting groups can also form a heterocyclic ring with thenitrogen to which they are attached, for example,1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl andthe like and where these heterocyclic groups can further includeadjoining aryl and cycloalkyl rings. In addition, the heterocyclicgroups can be mono-, di- or tri-substituted, such as nitrophthalimidyl.Amino groups may also be protected against undesired reactions, such asoxidation, through the formation of an addition salt, such ashydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.Many of the amino protecting groups are also suitable for protectingcarboxy, hydroxy and mercapto groups. For example, aralkyl groups. Alkylgroups are also suitable groups for protecting hydroxy and mercaptogroups, such as tert-butyl.

Silyl protecting groups are silicon atoms optionally substituted by oneor more alkyl, aryl and aralkyl groups. Suitable silyl protecting groupsinclude, but are not limited to, trimethylsilyl, triethylsilyl,tri-isopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of an amino groups provide mono- ordi-silylamino groups. Silylation of aminoalcohol compounds can lead to aN,N,O-tri-silyl derivative. Removal of the silyl function from a silylether function is readily accomplished by treatment with, for example, ametal hydroxide or ammonium fluoride reagent, either as a discretereaction step or in situ during a reaction with the alcohol group.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride,diphenylmethyl silyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

Protecting groups are removed under conditions which will not affect theremaining portion of the molecule. These methods are well known in theart and include acid hydrolysis, hydrogenolysis and the like. Apreferred method involves removal of a protecting group, such as removalof a benzyloxycarbonyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxycarbonyl protecting group can beremoved utilizing an inorganic or organic acid, such as HCl ortrifluoroacetic acid, in a suitable solvent system, such as dioxane ormethylene chloride. The resulting amino salt can readily be neutralizedto yield the free amine. Carboxy protecting group, such as methyl,ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can beremoved under hydroylsis and hydrogenolysis conditions well known tothose skilled in the art.

It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms, such as cyclic and acyclic amidineand guanidine groups, heteroatom substituted heteroaryl groups (Y′═O, S,NR), and the like, which are illustrated in the following examples:

and though one form is named, described, displayed and/or claimedherein, all the tautomeric forms are intended to be inherently includedin such name, description, display and/or claim.

Prodrugs of the compounds of this invention are also contemplated bythis invention. A prodrug is an active or inactive compound that ismodified chemically through in vivo physiological action, such ashydrolysis, metabolism and the like, into a compound of this inventionfollowing administration of the prodrug to a patient. The suitabilityand techniques involved in making and using prodrugs are well known bythose skilled in the art. For a general discussion of prodrugs involvingesters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) andBundgaard Design of Prodrugs, Elsevier (1985). Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bundgaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloanand Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acidprodrugs, their preparation and use. “Cytokine” means a secreted proteinthat affects the functions of other cells, particularly as it relates tothe modulation of interactions between cells of the immune system orcells involved in the inflammatory response. Examples of cytokinesinclude but are not limited to interleukin 1 (IL-1), preferably IL-1β,interleukin 6 (IL-6), interleukin 8 (IL-8) and TNF, preferably TNF-α(tumor necrosis factor-α).

“TNF, IL-1, IL-6, and/or IL-8 mediated disease or disease state” meansall disease states wherein TNF, IL-1, IL-6, and/or IL-8 plays a role,either directly as TNF, IL-1, IL-6, and/or IL-8 itself, or by TNF, IL-1,IL-6, and/or IL-8 inducing another cytokine to be released. For example,a disease state in which IL-1 plays a major role, but in which theproduction of or action of IL-1 is a result of TNF, would be consideredmediated by TNF.

Compounds according to the invention can be synthesized according to oneor more of the following methods. It should be noted that the generalprocedures are shown as it relates to preparation of compounds havingunspecified stereochemistry. However, such procedures are generallyapplicable to those compounds of a specific stereochemistry, e.g., wherethe stereochemistry about a group is (S) or (R). In addition, thecompounds having one stereochemistry (e.g., (R)) can often be utilizedto produce those having opposite stereochemistry (i.e., (S)) usingwell-known methods, for example, by inversion.

EXAMPLE 1

Tetrahydro-pyrimidin-2-ylideneamine hydrochloride: A suspension of1,3-diaminopropane (74 g, 1 mol) and guanidine hydrochloride (76 g, 0.8mol) was heated to 140° C. while stirring for 20 h. Reaction temperaturelowered to 100° C. and isopropyl alcohol (100 mL) added. At roomtemperature resulting solid collected by filtration and solid washedwith diethyl ether. Air dried overnight. White powder. M+1=100.

3-(3,4-Dimethyl-phenyl)-3-oxo-propionic acid methyl ester: To a stirringsolution of 3,4-dimethylacetophenone (1.0 g, 6.8 mmol) intetrahydrofuran (10 ML) at 0° C. under an atmosphere of nitrogen wasadded potassium hexamethyldisilylzide (1.46 g, 6.8 mmol). Resultingsuspension was stirred for 10 min and dimethylcarbonate (0.58 mL, 6.8mmol) added. Reaction stirred for 16 h warming to room temperature thenpoured onto wet ice (50 mL)/ hydrochloric acid (5 mL). Product extractedwith ethyl acetate (50 mL) and organic washed with saturated sodiumchloride then dried over magnesium sulfate. Product isolated as an amberoil after removal of solvent under vacuum. M+1=207.

2-(3,4-Dimethyl-phenyl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin4-one:A suspension of 3-(3,4-dimethyl-phenyl)-3-oxo-propionic acid methylester (1.2 g, 5.8 mmol), tetrahydro-pyrimidin-2-ylideneaminehydrochloride (0.78 g, 5.8 mmol), and potassium carbonate (0.80 g, 5.8mmol) in ethanol (20 mL) was heated to reflux for 4 h. Water (5 mL) wasadded to the reaction at room temperature and tan solid was collected byfiltration. M+1=256.

2-(3,4-Dimethyl-phenyl)-9-(2-methylsulfanyl-pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:A suspension of2-(3,4-dimethyl-phenyl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(400 mg, 1.6 mmol), 4-chloro-2-methylthiopyrimidinone (0.24 mL, 2.0mmol), palladium acetate (11 mg, 0.05 mmol),bis(diphenylphosphino)-1,1′-binaphthyl (37 mg, 0.05 mmol), and sodiumtert-butoxide (192 mg, 2.0 mmol) was heated to reflux in toluene (6 mL)under an atomosphere of nitrogen overnight. Reaction diluted with ethylacetate (50 mL) and organics washed with saturated ammonium chloride.Solvents removed under vacuum, and resulting pale yellow solids washedwith methanol/ diethyl ether (1:10, 2 mL). M+1=380.

2-(3,4-Dimethyl-phenyl)-9-(2-methanesulfonyl-pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:To a stirring solution of2-(3,4-Dimethyl-phenyl)-9-(2-methylsulfanyl-pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(260 mg, 0.69 mmol) in acetonitrile (2 mL) and trifluoroacetic acid (2mL) at 0° C. under an atmosphere of nitrogen was added urea hydrogenperoxide (129 mg, 1.37 mmol) and trifluoroacetic anhydride (0.20 mL, 1.4mmol). After 30 min, solvents removed under vacuum, and residue waspartitioned between dichloromethane (50 mL) and 5 % sodium bicarbonate(10 mL). Organic dried over magnesium sulfate, then concentrated to asolid under vacuum. M+1=412.

2-(3,4-Dimethyl-phenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:A suspension of2-(3,4-dimethylphenyl)-9-(2-methanesulfonyl-pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(150 mg, 0.36 mmol) and S-(−)-α-methylbenzylamine (1.3 mL, 10 mmol) washeated to 90° C. in dioxane (1 mL) for 5 h. Reaction concentrated undervacuum and purified on silica. Resulting pale yellow solid washed withmethanol/ diethyl ether (1: 10, 2 mL). M+1=453.

¹H NMR (CDCl₃) d (3H, 1.58 ppm), t (2H, 2.11 ppm), s (6H, 2.29 ppm), m(1H, 3.99 ppm), m (1H, 4.04 ppm), m (1H, 4.11 ppm), m (1H, 5.08 ppm), m(1H, 5.40 ppm), s (1H, 6.56 ppm), d (1H, 7.18 ppm), m (2H, 7.23 ppm), t(2H, 7.33 ppm), d (2H, 7.38 ppm), dd (1H, 7.62 ppm), s (1H, 7.67 ppm), d(1H, 8.13 ppm).

The examples in the following table were prepared using the abovemethod, but substituting 3,4-dimethylacetophenone with the appropriatemethyl ketone.

Example R¹ HPLC RT (method) MS M + 1 1 3,4-dimethylphenyl 7.41 (A) 453 22-fluorophenyl 7.06 (A) 443 3 2-trifluoromethylphenyl 7.32 (A) 493 44-fluorophenyl 7.06 (A) 443 5 4-methoxyphenyl 6.98 (A) 455 63-nitrophenyl 7.01 (A) 470 7 3-aminophenyl 5.64 (A) 440 83-dimethylaminephenyl 5.93 (A) 468 9 4-pyridyl N/A 425 10 phenyl N/A 42411 tert-butyl 7.03 (A) 405 12 3-ethylphenyl 7.53 (A) 453 133,4-dichlorophenyl 7.73 (A) 493

HPLC Method A: Luna C18 5 mm 100×4.6 mm; flow rate 1.0 mL/min withgradient of 0 min 5%→9 min 95%→9.5 min 95%-→10 min 5%. Solvent A: water(0.1% TFA); Solvent B: acetonitrile (0.1% TFA).

EXAMPLE 14

9-(2-Methylsulfanyl-pyrimidin-4-yl)-3-nitro-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:To a stirring solution of9-(2-methylsulfanyl-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(500 mg, 1.42 mmol) in dichloromethane (10 mL) at 0° C. under nitrogenwas added nitronium tetrafluoroborate in a 0.5M solution (7 mL, 3.55mmol). External cooling removed and reaction warmed to room temperaturewhile stirring for 1 h. Reaction washed with 5% sodium bicarbonate andsaturated ammonium chloride. Organic concentrated under vacuum andorange solid isolated after purification on silica. M+1=397.

9-(2-Methanesulfonyl-pyrimidin-4-yl)-3-nitro-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:To a stirring solution of9-(2-methylsulfanyl-pyrimidin-4-yl)-3-nitro-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(235 mg, 0.59 mmol) in acetonitrile (2 mL) and trifluoroacetic acid (2mL) at 0° C. under an atmosphere of nitrogen was added urea hydrogenperoxide (113 mg, 1.2 mmol) and trifluoroacetic anhydride (0.17 mL, 1.2mmol). After 30 min solvents removed under vacuum, and residue waspartitioned between dichloromethane (50 mL) and 5 % sodium bicarbonate(10 mL). Organic dried over magnesium sulfate, then concentrated to asolid under vacuum. M+1=429.

3-Nitro-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:A solution of9-(2-methanesulfonyl-pyrimidin-4-yl)-3-nitro-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(220 mg, 0.51 mmol) and phenethylamine (0.13 mL, 1.0 mmol) indichloromethane (2 mL) was heated to 80° C. for 1 h. Residue purified onsilica, and final product isolated as a white solid. M+1=470.

3-Amino-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:A suspension of3-nitro-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(40 mg, 0.09 mmol) in methanol (10 mL) was stirred with 10 % palladiumon carbon (5 mg) under an atmosphere of hydrogen for 4 h. Reactionmixture filtered through a bed of Celite, and final product isolated asa white solid after removal of solvent under vacuum. M+1=440 ¹NMR(CDCl₃) t (2H, 2.20 ppm), t (2H, 2.91 ppm), dd (2H, 3.67 ppm), s (2H,4.07 ppm), m (4H, 4.15 ppm), s (1H, 5.10 ppm), d (1H, 7.17 ppm), m (3H,7.24 ppm), m (2H, 7.31 ppm), m (1H, 7.36 ppm), t (2H, 7.46 ppm), d (2H,7.79 ppm), d (1H, 8.03 ppm).

3-Amino-9-{2-[2-(3-aminomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:To a solution of9-{2-[2-(3-azidomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-3-nitro-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(61 mg, 0.11 mmol) in 1 mL methanol was safely added 10 mg palladium oncarbon (10%) and stirred over an atmosphere of hydrogen delivered by aballoon. After 2 h, the reaction was filtered through a bed of Celiteand solvent removed under reduced pressure. Product was purified onsilica. M+1=483 1H NMR (CDCl₃) d (3H, 1.19 ppm), m (2H, 2.20 ppm), dd(1H, 2.76 ppm), dd (1H, 2.96 ppm), s (2H, 3.84 ppm), m (6H, 4.08 ppm), q(1H, 4.30 ppm), d (1H, 4.95 ppm), m (4H, 7.13 ppm), t (1H, 7.28 ppm), t(1H, 7.36 ppm), t (2H, 7.45 ppm), d (2H, 7.80 ppm), d (1H), 8.03 ppm).

The examples in the following table were prepared using the abovemethods, as indicated, using the appropirately substituted oxopropionicacid derivative from scheme A and the appropriate amine to replace thephenethylamine, if desired:

Exam- Synthetic HPLC RT MS ple R³ R⁴ Method (method) M + 1 14 —NH₂-ethyl-1-methyl-2(3- A, B, D, E 4.92 (A) 483 methylaminophenyl) 15 —NO₂-ethyl-2-phenyl A, B 7.09 (A) 470 16 —CH₃ -1-(S)-phenylethyl A 7.20 (A)439 17 —NH₂ -ethyl-2-(2- A, B 6.87 (A) 474 chlorophenyl) 18 —NH₂-ethyl-2-phenyl A, B 6.62 (A) 440

EXAMPLE 19

1-Bromo-3-(2-nitro-propenyl)-benzene: A suspension of3-bromo-benzaldehyde (2.5 g, 13.5 mmol), ammonium acetate (1.09 g, 14.2mmol), and nitroethane (250 mL) was heated to reflux overnight. Solventremoved under vacuum then residue partitioned between ethyl acetate andsaturated sodium chloride. Concentrated organic purified on silica andisolated as a yellow oil. ¹H NMR (CDCl₃) s (3H, 2.44 ppm), m (2H, 7.35ppm), m (2H, 7.55 ppm) s (1H, 8.00 ppm).

[2-(3-Bromo-phenyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester: To astirring solution of lithium aluminum hydride (24 mL of 1 M intetrahydrofuran (THF), 24 mmol) at 0° C. under an atmosphere of nitrogenwas added sulfuric acid (0.61 mL, 12.0 mmol) in tetrahydrofuran (10 mL)dropwise. Then a solution of 1-bromo-3-(2-nitro-propenyl)-benzene (1.17g, 4.8 mmol) in THF was added dropwise via an addition funnel. Reactionwarmed to room temperature overnight. Reaction chilled to 0° C., and asaturated solution of potassium sodium tartrate tetrahydrate added tothe reaction dropwise. Once a cake formed, the organic phase was reducedto an oil under vacuum. This residue was then dissolved indichloromethane and dried over magnesium sulfate.Di-tert-butyldicarbonate (1.05 g, 4.8 mmol) added and solution stirredovernight at room temperature. Reaction reduced to an oil under vacuumand isolated as a white solid after purification on silica. M+1=314/316.

[2-(3-Cyano-phenyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester: To asealed pressure tube was added[2-(3-bromo-phenyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (1.23g, 3.9 mmol), sodium cyanide (250 mg, 5.1 mmol), potassium iodide (130mg, 0.8 mmol), N-N′-dimethylethylenediamine (0.41 mL, 3.9 mmol), andtoluene (6 mL). This suspension was then sparged with nitrogen prior toadding copper iodide (150 mg, 0.8 mmol). Reaction mixture heated to 130°C. for 16 h while stirring. Reaction partitioned between ethyl acetateand 30% aqueous ammonia. Organic washed with saturated ammoniumchloride, then dried over magnesium sulfate. Reaction reduced to an oilunder vacuum and isolated as a white solid after purification on silica.M+1=261.

3-(2-Amino-propyl)-benzonitrile: A solution of[2-(3-Cyano-phenyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (180mg, 0.69 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (5 mL)was stirred for 15 min at room temperature. Solvents removed undervacuum, and residue was partitioned between dichloromethane and 1 Nsodium hydroxide. Organic dried over magnesium sulfate and reduced to anoil under vacuum. M+1=161.

{2-[3-(Benzhydrylidene-amino)-phenyl]-1-methyl-ethyl}-carbamic acidtert-butyl ester: A suspension of[2-(3-bromo-phenyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (750mg, 2.39 mmol), benzophenone imine (0.44 mL, 2.63 mmol), sodiumtert-butoxide (298 mg, 3.1 mmol), bis(diphenylphosphino)-1,1′-binaphthyl(45 mg, 0.07 mmol), palladium acetate (16 mg, 0.07 mmol), and toluene(7.5 mL) was heated to reflux for 3 h while stirring under an atmosphereof nitrogen. Reaction diluted with ether and organics washed with waterand saturated sodium chloride. Product isolated as a viscous yellow oilafter purification on silica. M+1=415.

3-(2-Amino-propyl)-phenylamine: A solution{2-[3-(Benzhydrylidene-amino)-phenyl]-1-methyl-ethyl}-carbamic acidtert-butyl ester (200 mg, 0.48 mmol) in dichloromethane (5 mL) andtrifluoroacetic acid (5 mL) was stirred for 45 min at room temperature.Solvents removed under vacuum and residue suspended in 5 N hydrochloricacid at 60° C. for 20 min. Biphasic system washed with ether andorganics discarded. The pH of the aqueous layer was then adjusted to 14with 10 N sodium hydroxide. Aqueous was then washed three times withdichloromethane (10 mL). Combined organics dried over magnesium sulfate,and product isolated as an amber film after removal of solvent undervacuum. M+1=151.

3-(2-Nitro-propenyl)-benzoic acid methyl ester: To a 250 mL round bottomflask was added 3-formyl-benzoic acid methyl ester (2.20 g, 13.4 mmol),ammonium acetate (1.03 g, 13.4 mmol), and nitroethane (60 mL). Mixtureheated to reflux under an atmosphere of nitrogen while stirring for 1.5h. Solvent removed under vacuum then residue partitioned between ethylacetate (100 mL) and 5% sodium bicarbonate. Organic washed withsaturated sodium chloride, dried with magnesium sulfate, thenconcentrated to a oil under vacuum. Product purified on silica andisolated as a yellow solid. ¹H NMR (CDCl₃) s (3H, 2.47 ppm), s (3H, 3.96ppmm), t (1H, 7.55 ppm), d (2H, 7.61 ppm) m (3H, 8.09 ppm).

[3-(2-Amino-propyl)-phenyl]-methanol: To a stirring suspension oflithium aluminum hydride (90 mL of 1 M in tetrahydrofuran (THF), 90mmol) at 0° C. under an atmosphere of nitrogen was added a solution of3-(2-nitro-propenyl)-benzoic acid methyl ester (2.03 g, 9.2 mmol) in THFwas added dropwise via an addition funnel over the course of 75 min.

Reaction warmed to room temperature overnight, chilled to 0° C., then asaturated solution of potassium sodium tartrate tetrahydrate added tothe reaction dropwise. Once a cake formed, the organic phase was removedand reduced to an oil under vacuum. This residue was then dissolved indichloromethane and dried over magnesium sulfate. Product purified onsilica and isolated as a colorless oil. M+1=166.

9-{2-[2-(3-Hydroxymethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:A mixture of9-(2-methanesulfonyl-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(344 mg, 0.90 mmol), [3-(2-amino-propyl)-phenyl]-methanol (371 mg, 2.25mmol), and N-methylmorpholine (8 mL) was heated to 100° C. for 20 h.Reaction was diluted with dichloromethane (15 mL) and ethyl acetate (40mL), washed three times with water (50 mL) then saturated sodiumchloride (10 mL). Organic dried over magnesium sulfate then concentratedto a oil under vacuum. Product purified on silica and isolated as awhite solid. M+1=469.

9-{2-[2-(3-Azidomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one: To astirring mixture of9-{2-[2-(3-hydroxymethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(230 mg, 0.49 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL, 0.88mmol), and tetrahydrofuran (12 mL) at 0° C. under an atmosphere ofnitrogen was added diphenylphosphoryl azide (0.19 mL, 0.88 mmol).Mixture stirred overnight warming to room temperature. Solvent removedunder vacuum and product isolated as a white solid after purification onsilica. M+1=494.

9-{2-[2-(3-Aminomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:To a nitrogen filled vessel containing a stirring solution of9-{2-[2-(3-azidomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(190 mg, 0.39 mmol) in methanol (25 mL) was added 10% palladium oncarbon (20 mg). Mixture stirred over an atmosphere of hydrogen. After 2h, reaction filtered through a bed of Celite and solvent removed undervacuum. Residue purified on silica and isolated as a white solid.

M+1=468. ¹NMR (CDCl₃) d (3H, 1.21 ppm), q (2H, 2.22 ppm), dd (1H, 2.77ppm), dd (1H, 2.98 ppm), s (2H, 3.85 ppm), m (4H, 4.12 ppm), q (1H, 4.30ppm), d (4.96 ppm), s (1H, 6.60 ppm), d (1H, 7.0 ppm), d (2H, 7.18 ppm),d (1H, 7.21 ppm), m(1H, 7.27 ppm), m (3H, 7.44 ppm), m (2H, 7.90 ppm), d(1H, 8.17 ppm).

9-(2-{2-[3-(Isopropylamino-methyl)-phenyl]-1-methyl-ethylamino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:A solution of9-{2-[2-(3-Aminomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(79 mg, 0.17 mmol) and acetone (0.015 mL, 0.21 mmol) was stirred for 10min prior to adding sodium borohydride (108 mg, 3.4 mmol). After 10 min,solvent removed under vacuum and residue partitioned betweendichloromethane (10 mL) and saturated sodium chloride. Product isolatedas a white solid after purification on silica. M+1=509.

Resolution of R/S Enantiomers:

9-{2-[2-(3-Aminomethyl-phenyl)-1(S)-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-oneand9-{2-[2-(3-aminomethyl-phenyl)-1(R)-methyl-ethylamino]-pyrimidin-4-yl l-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one: a sample of9-{2-[2-(3-aminomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one wasseparated via chiral HPLC employing a CHIRALPAK AS (10 μm 20×250 mm) andeluting with 0.2% diethylamine in methanol/ carbon dioxide (35:65) at 50mL/min (120 bar). The S-enantiomer was then confirmed by comparing theretention times on the above column to that of synthetic9-{2-[2-(3-aminomethyl-phenyl)-1(S)-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-oneutilizing synthetic schemes E and F.

(3-Bromobenzyloxy)-tert-butyldimethylsilane: A solution 3-bromobenzylalcohol (7.1 g, 38 mmol) and tert-butyldimethylsilyl chloride (5.7 g, 38mmol) in N,N-dimethylformamide (40 mL) was stirred at room temperaturefor 5 h. Water (40 mL) was added and the mixture was extracted withhexanes. The combined extracts were washed with 10% aqueous hydrochloricacid, saturated sodium bicarbonate, saturated sodium chloride, and driedover magnesium sulfate. The desired product was isolated afterconcentration and purification by silica gel chromatography (hexanes).¹H NMR (CDCl₃) 7.48 (s, 1H), 7.34 (m, 1H), 7.24 (m, 2H), 4.72 (s, 2H),0.95 (s, 9H), 0.11 (s, 6H).

1-[3-(Tert-butyldimethylsilyloxymethyl)-phenyl]-propan-2-ol: To astirring solution of (3-bromobenzyloxy)-tert-butyldimethylsilane (7.0 g,24 mmol) in tetrahydrofuran (100 mL) under an atmosphere of nitrogen wasadded magnesium turnings (0.73 g, 30 mmol) and a crystal of iodine. Themixture was heated to reflux for 1 h, cooled to 0° C. and copper (I)iodide (4.57 g, 24 mmol) was added. After stirring at 0° C. for 5 min,(R)-(+)-propylene oxide was added and the mixture was stirred for 2 h. Amixture of ammonium chloride and ammonium hydroxide (5:1, 100 mL) wasadded, the biphasic mixture was stirred vigorously until the coppersalts dissolved, and the layers were separated. The aqueous layer wasextracted with ethyl acetate, and the organic extracts were dried overmagnesium sulfate and purified by flash column chromatography (ethylacetate/hexanes). ¹H NMR (CDCl₃) 7.28 (m, 1H), 7.22 (m, 1H), 7.17 (s,1H), 7.10 (d, 1H) 4.73 (s, 2H), 4.00 (m, 1H), 2.77 (d, 1H), 2.70 (d,1H), 1.60 (s, 1H), 1.24 (d, 3H), 0.94 (s, 9H), 0.10 (s, 6H).

[3-(2-Azidopropyl)-benzyloxy]-tert-butyldimethylsilane: To a stirringsolution of 1-[3-(tert-butyldimethylsilyloxymethyl)-phenyl]-propan-2-ol(130 mg, 0.46 mmol) in THF (1.5 mL) under nitrogen at 0° C. was addeddiisopropyl azodicarboxylate (140 mg, 0.7 mmol), triphenylphosphine (180mg, 0.7 mmol), and diphenylphosphoryl azide (190 mg, 0.7 mmol) and themixture was stirred at 0° C. for 15 min. The mixture was diluted withdichloromethane, washed with water, brine, dried over magnesium sulfate,and purified by flash column chromatography (ethyl acetate/hexanes). ¹HNMR (CDCl₃) 7.27 (m, 1H), 7.2 (m, 1H), 7.16 (s, 1H), 7.08 (m, 1H), 4.74(s, 2H), 3.65 (m, 1H), 2.82 (dd, 1H), 2.73 (dd, 1H), 1.25 (d, 3H), 0.94(s, 9H), 0.10 (s, 6H).

2-[3(Tert-butyldimethylsilyloxymethyl)-phenyl]-1-methyl-ethylamine: To astirring solution of[3-(2-azidopropyl)-benzyloxy]-tert-butyldimethylsilane (100 mg, 0.33mmol) in THF (1 mL) and water (0.3 mL) at 0° C. was addedtriphenylphosphine (128 mg, 0.5 mmol) and the solution was stirred withwarming to room temperature overnight. The mixture was concentratedunder vacuum and purified by flash column chromatography(NH₃—MeOH/CH₂Cl₂). M+1=280.

[3-2-Aminopropyl)-phenyl]-methanol: To a stirring solution of2-[3(tert-butyldimethylsilyloxymethyl)-phenyl]-1-methyl-ethylamine (730mg, 2.6 mmol) in tetrahydrofuran (2 mL) was added tetrabutylammoniumfluoride (3.1 mmol) and the mixture was stirred at room temperature for2 h. The solvent was removed under vacuum and the product was obtainedafter flash column chromatography (NH₃—MeOH/CH₂Cl₂). ¹H NMR (CDCl₃) 7.30(m, 1H), 7.26 (m, 1H), 7.19 (s, 1H), 7.10 (d, 1H), 4.67 (s, 2H), 3.61(m, 1H), 2.71 (d, 1H), 2.51 (d, 1H), 1.67 (br s, 3H), 1.12 (d, 3H).

The examples in the following table were prepared using the abovemethods, as indicated, using the appropirately substituted oxopropionicacid derivative from scheme A and the appropriate amine to replace thephenethylamine, if desired:

Synthetic HPLC RT MS Example R⁴ Method (method) M + 1 191-(3-(N-methyl-N- A, D, E N/A 510 isopropyl-aminophenyl))- prop-2-yl 20-ethyl-2-ol A N/A 365 21 -ethyl-2-morpholino A 5.04 (A) 434 22-propyl-2-methyl A 6.62 (A) 377 23 -ethyl-2-methoxy A 5.81 (A) 379 24-ethyl-1(S)-methyl-2-ol A 5.56 (A) 379 25 -ethyl-1(S)-isopropyl-2-ol A6.45 (A) 421 26 -ethyl-2-phenoxy A 6.86 (A) 441 27-propyl-2,2-dimethyl-3- A 5.24 (A) 434 dimethylamino 28-ethyl-2-aminophenyl A 6.16 (A) 440 29 -benzyl A 6.70 (A) 411 30-propyl-3-phenyl A 7.04 (A) 439 31 -propyl-2(S)-amino-3- A 5.56 (A) 454phenyl 32 -ethyl-2-(2-chlorophenyl) A 6.97 (A) 459 33-ethyl-2-(2-methoxyphenyl) A 6.84 (A) 455 34 -ethyl-2-(4-methoxyphenyl)A 6.68 (A) 455 35 -ethyl-2-(4-methylphenyl) A 6.99 (A) 439 36-ethyl-2-(4-hydroxyphenyl) A 6.05 (A) 441 37 -ethyl-2-(3,4- A 7.19 (A)453 dimethylphenyl) 38 -hydrogen A 5.26 (A) 321 39 -ethyl-2-phenyl-2-olA 6.20 (A) 441 40 -ethyl-2-keto-2-phenyl A N/A 439 41 -propyl-1-phenyl AN/A 439 42 -ethyl-1-amido-2-phenyl A N/A 468 43-ethyl-1(S)methyl-2-phenyl A 6.66 (A) 439 44 -ethyl-1-methyl-2-(3- A, D,E 5.44 (A) 468 methylaminophenyl) 45 -ethyl-1-methyl-2-(3- A, C N/A 454aminophenyl) 46 -ethyl-1-methyl-2-(3- A, C 6.64 (A) 464 cyanophenyl) 47-ethyl-1-methyl-2-(3- A, D, E 6.70 469 methylalcoholphenyl) 48-ethyl-2-phenyl A 6.90 (A) 425 49 -ethyl-1(S)methyl-2-(3- A, D, E, F5.44 (A) 468 methylaminophenyl)

EXAMPLE 50

(5-Bromo-pyrimidin-2-yl)-bis-carbamic acid tert-butyl ester: Asuspension of 5-bromo-pyrimidin-2-ylamine (10.2 g, 58.6 mmol),di-tert-butyldicarbonate (28.1 g, 129 mmol), and pyridine (100 mL) washeated to 70° C. overnight while stirring under an atmosphere ofnitrogen. Solvent removed under vacuum, then residue was partitionedbetween diethyl ether and 5% potassium dihydrogenphosphate. Organicwashed with saturated ammonium chloride then dried over magnesiumsulfate. Partial evaporation of ether under vacuum produced a whitesolid which then was collected by filtration. M+1=374/376.

3-(2-bis-tert-Butoxycarbonylamino-pyrimidin-5-yl)-acrylic acidtert-butyl ester: A mixture of (5-bromo-pyrimidin-2-yl)-bis-carbamicacid tert-butyl ester (5.0 g, 13.4 mmol), tert-butylacrylate (3.9 mL,26.7 mmol), potassium acetate (3.9 g, 40.2 mmol), tetrabutylammoniumbromide (4.3g, 13.4 mmol), palladium acetate (150 mg, 0.7 mmol), andN-N′-dimethylformamide (50 mL) was stirred at 70° C. for 1 h. Solventremoved under vacuum, and residue partitioned between ether (200 mL) andwater. Organic washed further with water and saturated ammonium chloridethen dried over magnesium sulfate. Product isolated as a yellow solidafter purification on silica. M+1=422.

3-(2-Amino-1,4,5,6-tetrahydro-pyrimidin-5-yl)-propionic acid ethyl esterhydrochloride salt: A solution of3-(2-bis-tert-butoxycarbonylamino-pyrimidin-5-yl)-acrylic acidtert-butyl ester (3.0 g, 7.1 mmol) in dichloromethane (20 mL) andtrifluoroacetic acid (50 mL) was stirred at room temperature for 2 h.Solvents removed under vacuum and resulting solid suspended in 2 Mhydrochloric acid in diethyl ether (25 mL) and in ethanol (75 mL).Palladium hydroxide on carbon (20%) added to the nitrogen filled flaskand stirred for 3 days under a hydrogen atmosphere of hydrogen deliveredvia balloon. Reaction mixture filtered through a bed of Celite, andfiltrate concentrated to an amber oil under vacuum. M+1=200.

3-[6-Oxo-1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,3,4,6-tetrahydro-2H-pyrimido[1,2-a]pyrimidin-3-yl]-propionicacid: A solution of3-[6-oxo-1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,3,4,6-tetrahydro-2H-pyrimido[1,2-a]pyrimidin-3-yl]-propionicacid ethyl ester (240 mg, 0.46 mmol), 10% aqueous lithium hydroxide (0.2mL), and tetrahydrofuran (5 mL) was heated to 50° C. Reactionpartitioned between dichloromethane (50 mL) and 5% sodiumdihydrogenphosphate. Organic dried over magnesium sulfate, thenconcentrated to a white solid under vacuum. M+1=497.

{2-[6-Oxo-1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,3,4,6-tetrahydro-2H-pyrimido[1,2-a]pyrimidin-3-yl]-ethyl}-carbamicacid benzyl ester: A suspension of3-[6-Oxo-1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,3,4,6-tetrahydro-2H-pyrimido[1,2-a]pyrimidin-3-yl]-propionicacid (218 mg, 0.44 mmol), diphenylphosphoryl azide (0.095 mL, 0.44mmol), N—N′-diisopropylethyl amine (0.077 mL, 0.44 mmol), and toluene (5mL) was heated to reflux for 1 h. Benzyl alcohol (0.091, 0.88 mmol)added to reaction and continued to reflux for an additional 6 h. Afterremoval of solvent under vacuum, product isolated as a white solid afterpurification on silica. M+1=602.

7-(2-Amino-ethyl)-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:A solution of{2-[6-Oxo-1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,3,4,6-tetrahydro-2H-pyrimido[1,2-a]pyrimidin-3-yl]-ethyl}-carbamicacid benzyl ester (100 mg, 0.17 mmol), dichloromethane (5 mL) andmethanol (15 mL) was added 10% palladium on carbon (5 mg) and stirred atroom temperature over an atmosphere of hydrogen overnight. Reactionfiltered through a bed of Celite, and solvent removed under vacuum toafford a white solid. M+1=468.

7-(2-Isopropylamino-ethyl)-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:To a solution of7-(2-Amino-ethyl)-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(70 mg, 0.15 mmol), acetone (0.02 mL), dichloromethane (0.5 mL) andmethanol (0.5 mL) was added sodium triacetoxyborohydride (38 mg, 0.18mmol) Reaction stirred for 2 h at room temperature. Solvents removedunder vacuum. Residue partitioned between dichloromethane and 5% sodiumbicarbonate. Organics purified on silica to afford a white solid.M+1=510. ¹NMR (CDCl₃) d (6H, 1.17 ppm), m (2H, 1.68 ppm), m (1H, 2.32ppm), m (3H, 2.78 ppm), t (2H, 2.94 ppm), m (1H, 3.55 ppm), dd (2H, 3.70ppm), d (1H, 4.40 ppm), dd (1H, 4.53 ppm), m (1H, 5.10 ppm), s (1H, 6.60ppm), m (3H, 7.24 ppm), m (2H, 7.32 ppm), m (3H, 7.44 ppm), m (2H, 7.90ppm) d (1H, 8.18 ppm).

The examples in the following table were prepared using the abovemethods, as indicated, using the appropriate substituted alkene toreplace the tert-butylacrylate, if desired:

Synthetic HPLC RT MS Example R³ Method (method) M + 1 50-ethyl-2-amino(N- A, G, H 6.00 (B) 510 isopropyl) 51 -ethyl-2-amino A,G, H 5.57 (A) 468 52 -ethyl-2-carbamic acid A, G, H 7.38 (A) 602 benzylester 53 -ethyl-2-amino(N-benzyl) A, G, H 6.17 (A) 558 54 -propionicacid ethyl ester A, G, H 7.27 (A) 525 55 -propionic acid A, G, H 7.50(B) 497

Synthetic HPLC RT MS Example R⁴ Method (method) M + 1 56-ethyl-1(S)-phenyl A 6.42 (A) 385 57 -ethyl-2-phenyl A 6.34 (A) 385 58-propyl-2-methyl A 6.00 (A) 337

EXAMPLE 59

4,5-Dihydro-1H-imidazol-2-ylamine hydroiodic acid: Suspension of2-methylsulfanyl-4,5-dihydro-1H-imidazole hydroiodic acid (3.0 g, 12.3mmol) and 2M ammonia in methanol (20 mL) heated to 90° C. in a sealedtube overnight. Solvents removed under vacuum to afford a white solid.M+1=86.

Synthetic Example R¹ R² R³ Method MS M + 1 59 -phenyl H1-(3-hydroxymethyl- A, D, H 454 phenyl)prop-2-yl

HPLC Method A: 5-95% acetonitrile (0.1% trifluoroacetic acid) in 10 min@1 mL/min on Agilent Zorbax Exlipse XDB C-8 (4.6×150 mm 5 μm).

HPLC Method B: 5-95% acetonitrile (0.1% trifluoroacetic acid) in 14 min@1 mL/min on LunaC-18(4.6×150 mm 5 μm).

for the generic structure:

EXAMPLE 60

2-Amino-3-methyl-6-phenyl-3H-pyrimidin-4-one. A mixture of KOH (1.22 g,22 mmol), MeI (6.85 g, 48 mmol), and 2-amino-6-phenyl-3H-pyrimidin-4-one(2.62 g, 14 mmol) in EtOH (130 mL) was stirred at room temperature in astoppered 250 mL roundbottom flask for 3 days. An additional 6.85 g (48mmol) MeI was added and stirring was continued for 1 day. The solventwas removed under vacuum and the residue was dissolved in H₂O (35mL),warmed to 50° C., and 1N HCl was added dropwise until the soliddissolved completely. The solution was cooled to room temperature, madeslightly basic with saturated NaHCO₃, and the resulting white solid wasfiltered and dried under vacuum. M+1: 202.

3-Methyl-2-(2-methylsulfanyl-pyrimidin-4-ylamino)-6-phenyl-3H-pyrimidin-4-one.A mixture of 2-amino-3-methyl-6-phenyl-3H-pyrimidin-4-one (500 mg, 2.5mmol), NaOtBu (286 mg, 3 mmol), 4-chloro-2-thiomethylpyrimidine (477 mg,3 mmol), (2′-dicylohexylphosphanyl-biphenyl-2-yl)-dimethylamine (98 mg,0.24 mmol), and Pd₂(dba)₃ (113 mg, 0.12 mmol) in toluene (12 mL) washeated to 110° C. for 5 h, cooled to room temperature and diluted withsaturated NH₄Cl (12 mL). The layers were separated and the aqueous layerwas extracted with EtOAc (20 mL) one time and CH₂Cl₂ (20 mL) one time.The combined organic extracts were concentrated to less than 5 mL andthe resulting off-white solid was collected by filtration to give theproduct. M+1: 326.

2-(2-Methanesulfinyl-pyrimidin-4-ylamino)-3-methyl-6-phenyl-3H-pyrimidin-4-one.M-CPBA (91 mg, 0.5 mmol) was added to a solution of3-methyl-2-(2-methylsulfanyl-pyrimidin-4-ylamino)-6-phenyl-3H-pyrimidin-4-one(115 mg, 0.35 mmol) in CH₂Cl₂ (2 mL) and the mixture was stirred at roomtemperature for 15 min, then quenched with saturated NaHCO₃. The layerswere separated and the aqueous layer was extracted with CH₂Cl₂ twotimes. The combined organic extracts were dried (MgSO₄), filtered, andconcentrated under vacuum. This material was combined with materialobtained from a second reaction on 472 mg of starting material. Thecombined material was purified via column chromatography to give theproduct. M+1: 342.

2-{2-[2-(3-Hydroxymethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-ylamino}-3-methyl-6-phenyl-3H-pyrimidin-4-one.A mixture of [3-(2-amino-propyl)-phenyl]-methanol (300 mg, 1.8 mmol) and2-(2-methanesulfinyl-pyrimidin-4-ylamino)-3-methyl-6-phenyl-3H-pyrimidin-4-one(300 mg, 0.9 mmol) in NMP (8 mL) was heated to 100° C. for 16 h. Thereaction was cooled to room temperature and EtOAc was added. The mixturewas then washed with H₂O three times, brine once, dried (MgSO₄),filtered, concentrated under vacuum, and purified by preparative-scaleTLC to give the product. M+1: 443.

2-{2-[2-(3-Azidomethyl-phenyl)-1-ethylamino]-pyrimidin-4-ylamino}-3-methyl-6-phenyl-3H-pyrimidin-4-one.A mixture of diphenylphosphoryl azide (237 mg, 0.86 mmol),1,8-diazabicylco[5.4.0]undec-7-ene (130 mg, 0.86 mmol), and2-{2-[2-(3-hydroxymethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-ylamino}-3-methyl-6-phenyl-3H-pyrimidin-4-one(190 mg, 0.43mmol) in THF (3.5 mL) was stirred at 35° C. for 17.5 h. Themixture was cooled to room temperature, diluted with H₂O, and extractedwith CH₂Cl₂ three times. The combined extracts were dried (MgSO₄),filtered, concentrated under vacuum, and purified by columnchromatography to give the product. M+1: 468.

2-{-[2-(3-Aminomethyl-phenyl)-1-methyl-ethylamino]-pyrimidine-4-ylamino}-3-methyl-6-phenyl-3H-pyrimidin-4-one.A mixture of Zn° powder (60 mg, 0.9 mmol), NH₄Cl (49 mg, 0.9 mmol), and2-{2-[2-(3-azidomethyl-phenyl)-1-ethylamino]-pyrimidin-4-ylamino}-3-methyl-6-phenyl-3H-pyrimidin-4-one(216 mg, 0.46 mmol) in a mixture of H₂O (2 mL) and EtOH (2 mL) washeated to reflux for 2 h and cooled to room temperature. The mixture waspartitioned between H₂O and 4:1 CHCl₃/IPA, the layers were separated andthe aqueous layer was extracted with 4:1 CHCl₃/IPA three times. Theextracts were dried (MgSO₄), filtered, concentrated, and purified bypreparative-scale TLC (30 mg, 15%). ¹H NMR (400 MHz, CDCl3): 8.14 (d, J4, 1H), 7.68 (s, 2H), 7.53 (m, 1H), 7.45 (m, 2H), 7.19 (m, 1H), 7.13 (d,J 16, 1H), 7.04 (s, 1H), 6.95 (s, 1H), 6.40 (br s, 1H), 6.10 (br s, 1H),4.62 ( br s, 1H), 4.18 (br s, 1H), 3.78 (s, 2H), 3.61 (s, 3H), 2.74 (brs, 2H), 1.11 (d, J 6, 3H). M+1: 442.

EXAMPLE 611-(2-{2-[4-(1-Amino-ethyl)-phenyl]-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,23,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:

1-(4-Bromo-phenyl)-ethyl]-carbamic acid ester: A mixture of1-(4-bromo-phenyl)-ethylamine (7.0 g, 35 mmol), di-tert-butyldicarbonate(35 mL, 1.0 M in THF), and triethylamine (4.9 mL, 35 mmol) in THF (140mL) was stirred at room temperature for 17 h. The mixture was washedwith saturated NH₄Cl, brine, dried over magnesium sulfate andconcentrated to afford a white solid as the desired product. M+1=300.

3-[4-(1-tert-Butoxycarbonylamino-ethyl)-phenyl]-acrylic acid ethylester: To a mixture of [1-(4-bromo-phenyl)-ethyl]-carbamic acidtert-butyl ester (3.0 g, 10 mmol), tris(dibenzylideneacetone)dipalladium(0.55 g, 0.6 mmol), and N-methyldicyclohexylamine (2.1 mL, 10 mmol) waspurged nitrogen followed by the addition of 1,4-dioxane (20 mL) andtri-tert-butylphospine (0.24 g, 1.2 mmol). The mixture was again purgedwith nitrogen and the ethyl acrylate (2.16 mL, 20 mmol) was added. Themixture was heated to 80° C. for 30 min, poured into water (100 mL) andextracted with ethyl acetate (150 mL). The organic layer was separated,washed again with water, dried over magnesium sulfate, concentrated andchromatographed on silica gel using 2:1 hexanes/ethyl acetate to afforda light-brown oil. M+1=320.

3-[4-(1-tert-Butoxycarbonylamino-ethyl)-phenyl]-propionic acid ethylester: Through a mixture of3-[4-(1-tert-butoxycarbonylamino-ethyl)-phenyl]-acrylic acid ethyl ester(0.22 g, 0.69 mmol) and palladium hydroxide on carbon (100 mg) inethanol (10 mL) was bubbled hydrogen through a balloon for 17 h. Themixture was filtered through celite and concentrated to afford anoff-white solid. M+1=322.

3-[4-(tert-Butoxycarbonylamino-ethyl)-phenyl]-propionic acid: Themixture of 3-[4-(1-tert-butoxyarbonylamino-ethyl)-phenyl]-propionic acidethyl ester (8.69 g, 27 mmol) and 1 N sodium hydroxide (135 mL, 135mmol) in methanol (50 mL) was heated to reflux for 1 h, brought to roomtemperature and concentrated. The residue obtained was dissolved inethyl acetate (50 mL) and the mixture was acidified to a pH 6-5 with 1Nhydrochloric acid. The organic phase was separated and concentrated toafford an off-white solid. M+1═294.

{1-[4-(2-Azidocarbonyl-ethyl)-phenyl]-ethyl}-carbamix acid tert-butylester: To a mixture of3-[4-(1-tert-butoxycarbonylamino-ethyl)-phenyl]-propionic acid (1.0 g,3.4 mmol) in dry THF (10 mL) at 0° C. was added triethylamine (0.8 mL).After 30 min, ethyl chloroformate was added dropwise. The mixture wasstirred at 0° C. for 1 h then, sodium azide (0.24 g, 3.74 mmol) in water(2 mL) was added dropwise. The ice-bath was removed and the mixture wasstirred at room temperature for 1.5 h. The mixture was diluted withethyl acetate (100 mL), washed with saturated sodium bicarbonate, brine,dried over magnesium sulfate and concentrated to afford a white solid.M+1=319.

{1-[4-(2-Benzyloxycarbonylamino-ethyl)-phenyl]-ethyl}carbamic acidtert-butyl ester: The mixture of{1-[4-(2-azidocarbonyl-ethyl)-phenyl]-ethyl}-carbamic acid tert-butylester (2.2 g, 6.92 mmol) and benzyl alcohol (1.0 mL, 10.4 mmol) intoluene (20 mL) was heated to 105° C. for 17 h. The mixture was broughtto room temperature and a white solid crashed out which corresponded tothe desired product. This solid was filtered off, washed with tolueneand dried under high vacuum. M+1=399.

{1-[4-(2-Amino-ethyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester: Themixture of {1-[4-(2-benzyloxycarbonylamino-ethyl)-phenyl]-ethyl}carbamicacid tert-butyl ester (0.80 g, 2.0 mmol), 1,4-cyclohexadiene (0.96 mL,10 mmol) and palladium on carbon (100 mg) in ethanol (20 mL)-methanol (5mL) was heated to reflux for 2 h and brought to room temperature. Themixture was filtered through celite and concentrated to afford a whitesolid. M+1=265.

[1-(4-{2-[4-(4-Oxo-8-phenyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)-pyrimidin-2-ylamino]ethyl}-phenyl)-ethyl]-carbamicacid tert-butyl ester: The mixture of1-(2-methanesulfonyl-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(0.20 g, 053 mmol) and {1-[4-(2-amino-ethyl)-phenyl]-ethyl}-carbamicacid tert-butyl ester (0.304 g, 0.79 mmol) in 1:1 dioxane:1-methyl-2-pyrrolidinone (6 mL) was heated to 100° C. for 17 h. Themixture was partitioned between water (10 mL) and ethyl acetate (20 mL).The organic phase was separated, washed with water, saturated sodiumbicarbonate, brine, dried over magnesium sulfate and chromatographed onsilica gel using 0-4% MeOH/CH₂Cl₂to afford a white solid. M+1=568.

1-(2-{2-[4-(1-Amino-ethyl)-phenyl]-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,23,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:The mixture of[1-(4-{2-[4-(4-oxo-8-phenyl)-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)-pyrimidin-2-ylamino]ethyl}-phenyl)-ethyl]-carbamicacid tert-butyl ester (0.24 g, 0.42 mmol) and trifluoroacetic acid (0.7mL, 20 mmol) in dichloromethane (5 mL) was stirred at room temperaturefor 1.5 h. The mixture was washed with saturated sodium bicarbonate,brine, dried over magnesium sulfate, concentrated and chromatographed onsilica gel using 0-8% 2M NH₃ MeOH/CH₂Cl₂ to afford a white solid.M+1=468. ¹NMR (DMSO) d (3H, 1.21 ppm), m (2H, 2.15 ppm), t (2H, 2.83ppm), d (1H, 3.18 ppm), b (2H, 3.49 ppm), m (6H, 4.13 ppm), s (1H, 6.62ppm), d (2H, 7.09 ppm), d (2H, 7.16 ppm), d (2H, 7.27 ppm), m (3H, 7.46ppm), dd (2H, 7.96 ppm), b (1H, 8.18 ppm).

EXAMPLE 621-(2-{2[4-(1-Isopropylamino-ethyl)-phenyl]-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

1-(2-{2[4-(1-Isopropylamino-ethyl)-phenyl]-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:The mixture of1-(2-{2-[4-(1-amino-ethyl)-phenyl]-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,23,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(70 mg, 0.15 mmol), sodium triacetoxyborohydride (0.13 g, 0.60 mmol),acetone (5 mL) and acetic acid (0.5 mL) in methanol (10 mL) was stirredat room temperature for 17 h. The mixture was concentrated and theresidue was dissolved in CH₂Cl₂ (50 mL), washed with saturated sodiumbicarbonate, brine, dried over magnesium sulfate and concentrated toafford a white solid. M+1=510. ¹H NMR (DMSO) dd (6H, 0.92 ppm), d (3H,1.19 ppm), m (2H, 2.14 ppm), m (1H, 2.44 ppm), t (2H, 2.82 ppm), b (2H,3.48 ppm), m (1H, 3.77 ppm), m (4H, 4.03 ppm), s (1H, 6.62 ppm), d (2H,7.08 ppm), d (2H, 7.16 ppm), d (2H, 7.24 ppm), m (3H, 7.46 ppm), dd (2H,7.96 ppm), b (1H, 8.18 ppm).

EXAMPLE 631-{2-[2-(4-Aminomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

4-(2-Nitro-propenyl)-benzoic acid methyl ester: The mixture of4-formyl-benzoic acid methylester (20.1 g, 122.4 mmol), ammonium acetate(9.4 g, 122.4 mmol) in nitroethane (200 mL) was heated to reflux for 2.5h. The mixture was brought to room temperature and concentrated. Theresidue was partitioned between water (200 mL) and ethylacetate (500mL). The organic layer was separated, washed with saturated sodiumbicarbonate, brine, dried over magnesium sulfate, concentrated andchromatographed on silica gel using 6:1 hexanes/ethylacetate to afford ayellow solid. M+1=222.

[4-(2-Amino-propyl-phenyl]-methanol: The suspension of lithiumaluminumhyride (11 g, 277 mmol) in THF (200 mL) was brought to 0° C.followed by the slowly addition of 4-(2-nitro-propenyl)-benzoic acidmethyl ester (12.25 g, 55.4 mmol) in THF (100 mL). Once the addition wascompleted, the mixture was stirred at 0° C. for 15 min and brought toroom temperature and stirred for 17 h. The mixture was brought to 0° C.and quenched with solid sodium sulfate decahydrate until stoppedbubbling. The suspension was filtered and the filtrate was concentratedand the yellow oil obtained was chromatographed on silica gel using 0-8%2M NH₃ MeOH/CH₂Cl₂. M+1=166.

1-{2-[2-(4-Hydroxymethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:1-(2-methanesulfonyl-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(1.1 g, 2.9 mmol) and [4-(2-amino-propyl)-phenyl]-methanol (0.96 g, 5.8mmol) in 1:1 dioxane: 1-methyl-2-pyrrolidinone (16 mL) was heated to100° C. for 20 h. The mixture was partitioned between water (30 mL) andethyl acetate (60 mL). The organic phase was separated, washed withwater, saturated sodium bicarbonate, brine, dried over magnesium sulfateand chromatographed on silica gel using 0-8% 2M NH₃ MeOH/CH₂Cl₂ toafford a white solid. M+1=469. ¹NMR (CDCl₃) d (3H, 1.21 ppm), s (1H,1.79 ppm), m (2H, 2.22 ppm), m(1H, 2.79 ppm), m (1H, 2.98 ppm), m (4H,4.11 ppm), m (1H, 4.13 ppm), b(3H, 4.68 ppm), s (1H, 6.60 ppm), d (2H,7.21 ppm), d (3H, 7.29 ppm), m (3H, 7.44 ppm), dd (2H, 7.91 ppm), d (1H,8.17 ppm).

1-{2-[2-(4-Azidomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:The mixture of1-{2-[2-(4-hydroxymethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(0.11 g, 0.24 mmol) and 1,8-diaza-bicyclo[5.4.0]undec-7-ene (47 μL,0.312 mmol) in tetrahydrofuran (5 mL) was brought to 0° C. followed bythe addition of diphenylphosphoryl azide (68 μL, 0.312 mmol). Themixture was removed from the ice-bath and stirred at room temperaturefor 17 h. The mixture was concentrated and chromatographed on silica gelusing 0-8% 2M NH₃ MeOH/CH₂Cl₂to afford a white solid. M+1=494.

1-{2-[2-(4-Aminomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:The mixture of1-{2-[2-(4-azidomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one,1,4-cyclohexadiene (80 μL, 0.80 mmol) and palladium on carbon (100 mg)in ethylacetate (10 mL) was heated to reflux for 3 h and brought to roomtemperature. The mixture was filtered through celite and concentrated toafford a white solid. M+1=468. ¹NMR (CDCl₃) d (3H, 1.22 ppm), m (2H,2.23 ppm), m (1H, 2.76 ppm), m (1H, 2.98 ppm), s (2H, 3.84 ppm), m (4H,4.11 ppm), m (1H, 4.31 ppm), d (1H, 4.95 ppm), s (1H, 6.60 ppm), d (2H,7.21 ppm), d (3H, 7.23 ppm), m (3H, 7.44 ppm), dd (2H, 7.91 ppm), d (1H,8.18 ppm).

EXAMPLE 641-(2-{2-[4-(2-Amino-propyl)-phenyl]-1-methyl-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

4-{2-[4-(4-Oxo-8-phenyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)-pyrimidin-2-ylamino]-propyl}-benzaldehyde:The mixture of1-{2-[2-(4-hydroxymethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(0.38 g, 0.81 mmol) and manganese dioxide (3.5 g, 40.5 mmol) indichloromethane was stirred at room temperature for 3 h. The mixture wasfiltered off and concentrated to afford a white solid. M+1=467.

1-(2-{1-Methyl-2-[4-(2-nitro-propenyl)-phenyl]-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:The mixture of4-{2-[4-(4-oxo-8-phenyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)-pyrimidin-2-ylamino]-propyl}-benzaldehyde(35 mg, 0.08 mmol), ammonium acetate (10 mg, 0.16 mmol) in nitroethane(5 mL) was heated to reflux for 4 h. The mixture was brought to roomtemperature and concentrated. The residue was dissolved in ethylacetate(20 mL), washed with water, saturated sodium bicarbonate, brine, driedover magnesium sulfate and concentrated. M+1=524.

1-(2-{2-[4-(2-Amino-propyl)-phenyl]-1-methyl-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:Through a mixture of1-(2-{1-methyl-2-[4-(2-nitro-propenyl)-phenyl]-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(10 mg, 0.02 mmol) and palladium on carbon (cat) in methanol was bubbledhydrogen through a balloon for 17 h. The mixure was filtered throughcelite, concentrated and chromatographed on silica gel using 0-4%MeOH/CH₂Cl₂ to afford an off-white solid. M+1=496. ¹NMR (CDCl₃) d (3H,1.28 ppm), d (3H, 1.79 ppm), m (1H, 1.86 ppm), m (2H, 2.22 ppm), m (1H,2.80 ppm), m (1H, 2.94 ppm), m (3H, 3.75 ppm), m (4H, 4.15 ppm), m (1H,4.30 ppm), s (1H, 6.60 ppm), d (3H, 7.15 ppm), d (2H, 7.22 ppm), m (3H,7.44 ppm), dd (2H, 7.91 ppm), d (1H, 8.17 ppm).

EXAMPLE 651-(2-{2-[3-(1-Amino-1-methyl-ethyl)-phenyl]-1-methyl-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

2-(3-Bromo-phenyl)-propan-2-ol: The 3-bromo-benzoic acid methyl ester(1.0 g, 4.7 mmol) in tetrahydrofuran (10 mL) was brought to −78° C.followed by the addition of methyl magnesium bromide (7.7 mL, 10.81mmol) and warmed to room temperature and stirred for 17 h. The mixturewas poured into sat NH₄Cl and extracted with ethylacetate. The organicextracts were combined, washed with brine, dried over magnesium sulfateand chromatographed on silica gel using 04% methanol/dichloromethane toafford colorless oil.

N-[1-(3-Bromo-phenyl)-1-methyl-ethyl]-2-chloro-acetamide: To a mixtureof the 2-(3-bromo-phenyl)-propan-2-ol and (0.76 g, 3.6 mmol) andchloro-acetonitrile (7 mL) was added acetic acid (0.6 mL) and theresulting mixture was cooled to 0° C. Concentrated sulfuric acid (0.6mL) was added dropwise and the mixture was brought to room temperatureand stirred for 17 h. Mixture was poured into ice-water (10 mL) andextracted with ethylacetate. The extracts were combined, dried overmagnesium sulfate and concentrated to afford a white solid. M+1=291.

1-(3-Bromo-phenyl)-1-methyl-ethylamine: The mixture ofN-[1-(3-bromo-phenyl)-1-methyl-ethyl]-2-chloro-acetamide (1.0 g, 3.5mmol), thiourea (0.32 g, 4.2 mmol), acetic acid (1.5 mL) in ethanol (7mL) was heated to reflux for 10 h and brought to room temperature. Waterwas added to the mixture until a precipitate was formed which wasfiltered. The filtrate was made basic pH 7-8 with 15% NaOH. The productwas extracted with ethyl acetate and concentrated to afford a yellowsolid. M+1=214.

3-[3-(1-Amino-1-methyl-ethyl)-phenyl]-2-methyl-acrylic acid methylester: The mixture of 1-(3-bromo-phenyl)-1-methyl-ethylamine (0.74 g,3.5 mmol), tris(dibenzylideneacetone)dipalladium (0.19 g, 0.21 mmol),and N-methyldicyclohexylamine (10 mmol) was purged with nitrogenfollowed by the addition of 1,4-dioxane (7 mL) andtri-tert-butylphospine (85 mg, 0.42 mmol). The mixture was again purgedwith nitrogen and ethyl acrylate (0.75 mL, 7.0 mmol) was added. Themixture was heated to 80° C. for 1 h, brought to room temperature,poured into water (50 mL) and extracted with ethyl acetate (100 mL). Theorganic layer was separated, washed again with water, dried overmagnesium sulfate, concentrated and chromatographed on silica gel using0-4% MeOHI/CH₂Cl₂ to afford yellow oil.

3-[3-(1-Amino-1-methyl-ethyl)-phenyl]-2-methyl-propionic acid methylester: The mixture of3-[3-(1-amino-1-methyl-ethyl)-phenyl]-2-methyl-acrylic acid methyl ester(2.0 g, 8.6 mmol), magnesium (0.63 g, 25.8 mmol) in methanol was heatedto reflux for 3 h until the starting material was consumed. The mixturewas brought to room temperature, filtered and the filtrate wasconcentrated. The residue obtained was washed with saturated NH₄Cl,brine, dried over magnesium sulfate and concentrated.

3-[3-(1-tert-Butoxycarbonylamino-1-methyl-ethyl)-phenyl]-2-methyl-propionicacid methyl ester: To a mixture of3-[3-(1-amino-1-methyl-ethyl)-phenyl]-2-methyl-propionic acid methylester (1.17 g, 5.0 mmol) in THF was added triethylamine (1 mL) andstirred at room temperature for 15 min followed by the addition of(Boc)₂O and dimethylaminopropylamine (cat.). The resulting mixture wasstirred at room temperature for 17 h. The mixture was poured into ethylacetate (200 mL) and washed with saturated NH₄Cl, brine, dried overmagnesium sulfate and chromatographed on silica gel using 0-4%methano/dichloromethane and 7% 2M NH₃ MeOH/CH₂Cl₂ to afford a yellowoil. M+1=336.

3-[3-1-tert-Butoxycarbonylamino-1-methyl-ethyl)-phenyl]-2-methyl-propionicacid: A mixture of3-[3-(1-tert-butoxycarbonylamino-1-methyl-ethyl)-phenyl]-2-methyl-propionicacid methyl ester (430 mg, 1.3 mmol) and 1 N sodium hydroxide (6.5 mL,6.5 mmol) in methanol (10 mL) was heated to reflux for 48 h. The mixturewas brought to room temperature and concentrated. The residue wasdissolved in dichloromethane (20 mL) and acidified to a pH ˜5 using 10%KHSO₄. The organic phase was separated and concentrated. M+1=322.

{1-[3-(2-Azidocarbonyl-propyl)-phenyl]-1-methyl-ethyl}-carbamic acidtert-butyl ester: To a stirred solution of3-[3-1-tert-butoxycarbonylamino-1-methyl-ethyl)-phenyl)-2-methyl-propionicacid (0.33 g, 1.03 mmol) in dry THF (5 mL) at 0° C. was addedtriethylamine (0.29 mL, 2.06 mmol). After 40 min, ethyl chloroformate(0.11 mL) was added dropwise. The mixture was stirred at 0° C. for 1.5 hthen, sodium azide (73 mg, 1.13 mmol) in water (0.5 mL) was addeddropwise. The mixture was brought to room temperature and stirred for1.5 h more. The resulting mixture was diluted with ethyl acetate (20mL), washed with saturated sodium bicarbonate, brine, dried overmagnesium sulfate and concentrated to afford yellow oil.

{1-[3-(2-Benzyloxycarbonylamino-propyl)-phenyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester: The mixture of{1-[3-(2-azidocarbonyl-propyl)-phenyl]-1-methyl-ethyl}-carbamic acidtert-butyl ester (0.34 g, 0.98 mmol) and benzyl alcohol (0.15 mL, 1.5mmol) in toluene (2 mL) was heated to 105° C. for 17 h. The mixture wasbrought to room temperature, concentrated and chromatographed on silicagel using 0-4% MeOlUCH₂Cl₂ to afford a light yellow solid.

{1-[3-(2-Amino-propyl)-phenyl]-1-methyl-ethyl}-carbamic acid tert-butylester: To a mixture of{1-[3-(2-benzyloxycarbonylamino-propyl)-phenyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester (0.28 g, 0.65 mmol), 1,4-cyclohexadiene (0.31 mL,3.25 mmol) and Pd/C (cat.) in methanol was heated to reflux for 17 h.The mixture was filtered through celite and concentrated to afford lightyellow oil. M+1=293.

[1-Methyl-1-(3-{2-[4-(4-oxo-8-phenyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)-pyrimidin-2-ylamino]-propyl}-phenyl)-ethyl]-carbamicacid tert-butyl ester: To a mixture of{1-[3-(2-amino-propyl)-phenyl]-1-methyl-ethyl}-carbamic acid tert-butylester (0.19 g, 0.65 mmol) and1-(2-methanesulfonyl-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(0.26 g, 0.72 mmol) in NMP (2 mL) was heated to 100° C. for 17 h. Themixture was poured into water (15 mL) and extracted with ethyl acetate.The organic extracts were combined, washed with saturated sodiumbicarbonate, brine, dried over magnesium sulfate and chromatographed onsilica gel using 0-4% MeOH/CH₂Cl₂ to afford a light yellow oil. M+1=596.

1-(2-{2-[3-(1-Amino-1-methyl-ethyl)-phenyl]-1-methyl-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:To a mixture of[1-methyl-1-(3-{2-[4-(4-oxo-8-phenyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)-pyrimidin-2-ylamino]-propyl}-phenyl)-ethyl]-carbamicacid tert-butyl ester (0.25 g, 0.42 mmol) and trifluoroacetic acid (1mL) in dichloromethane (2 mL) was stirred at room temperature for 30min. The mixture was washed with saturated sodium bicarbonate, brine,dried over magnesium sulfate and was purified by chromatography onsilica gel using 0-8% 2 M NH₃ MeOH/CH₂Cl₂. M+1=496. ¹NMR (CDCl₃) d (3H,1.23 ppm), s (6H, 1.47 ppm), m (2H, 2.21 ppm), m (1H, 2.82 ppm), m (1H,2.98 ppm), s (1H, 3.48 ppm), m (4H, 4.12 ppm), m (1H, 4.35 ppm), d (1H,4.95 ppm), s (1H, 6.60 ppm), d (1H, 7.09 ppm), d (1H, 7.21 ppm), m (2H,7.36 ppm), m (3H, 7.44 ppm), dd (2H, 7.91 ppm), d (1H, 8.16 ppm).

for the general structure:

EXAMPLE 667-Hydroxy-2-phenyl-9-[2-(1-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

2-Imino-hexahydro-pyrimidin-5-ol hydrochloride: A mixture of2-hydroxy-1,3-diaminopropane (9.80 g, 108 mmol) and guanidinehydrochloride (10.4 g, 108 mmol) in a 100 mL RBF was heated at 140° C.under nitrogen for 5 h. The reaction mixture, while under vigorousstirring, was let cooled to 100° C. whereby a mixture of iPrOH (5 mL)and CH₃CN (5 mL) were added, resulting in the formation of a slurry.After cooled to room temperature, the mixture was filtered and the solidwas washed with additional CH₃CN (total 30 mL). The solid was furtherdried under vacuum to yield a white solid. ¹H NMR (400 MHz, D₂O): 4.21(m, 1 H), 3.34 (dt, J 15.2, 2.8, 2H), 3.22 (dt, J 15.2, 2.8).

7-Hydroxy-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one: Ina 250 mL RBF with a stirrer bar, a mixture of 3-oxo-3-phenyl-propionicacid ethyl ester (15 g, 78 mmol), K₂CO₃ (11.0 g, 80 mmol) and2-imino-hexahydro-pyrimidin-5-ol hydrochloride (11.8 g, 78 mmol) in EtOH(150 mL) was heated at 90° C. under nitrogen overnight. After 17 h, themixture was cooled to room temperature, and filtered. The mother liquidwas concentrated to a sludge that was then diluted with H₂O. Theresulting slurry was filtered and the solid was washed first with MeOH,then a mixture of EtOAc-MeOH (2:1) to give the first batch of product.The solid residue from the crude reaction was washed first with H₂O(3×10 mL), then MeOH, and finally a mixture of EtOAc-MeOH (2: 1) toyield a second batch of product. The combined products were the dried inair to provide a white solid. ¹H NMR (400 MHz, DMSO₆): 7.94 (m, 2 H),7.44 (bt, J 3.2, 0.5 H), 6.10 (s, 1H), 5.35 (d, J 3.2, 0.5 H), 4.22 (m,1 H), 4.12 (d, J 14,1H), 3.54 (dd, J 14, 2.0,1 H), 3.39 (d, 12.4, 1H),3.18 (m, 1H). M+1: 244.

7-(tert-Butyl-dimethyl-silanyloxy)-9-(2-methylsulfanyl-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

7-(tert-Butyl-dimethyl-silanyloxy)-2-phenyl-6,7,8,9-tetrahydro-pyrimido1,2-a]pyrimidin-4-one: A mixture of the alcohol (1.0 g, 4.1 mmol),TBDMSCl (1.3 g, 6.1 mmol), and imidazole (0.80 g, 12 mmol) in DMF (9 mL)was stirred at room temperature. After 5 h, the reaction mixture wasdiluted with EtOAc (50 mL). The organic was washed with H₂O (3×20 mL),dried (Na₂SO₄) and concentrated to a solid. M+1: 358

In a 150 mL RBF with a stirrer bar, 4-chloro-2-methylsulfanyl-pyrimidine(1.0 g, 9.3 mmol) and7-(tert-butyl-dimethyl-silanyloxy)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(1.0 g, 2.8 mmol) were mixed in PhMe (12 mL) and dioxane (3 mL) undernitrogen. Subsequently BINAP (0.18 g, 0.28 mmol), Pd(OAc)₂ (0.063 g.0.28 mmol), and NaOtBu (0.54 g, 5.6 mmol) were added. The mixture washeated to 110° C. with vigorous stirring for 4 h. After cooled to roomtemperature, the mixture was diluted with EtOAc (50 mL) and theresulting mixture was washed with H₂O, NH₄Cl (sat), and dried withNa₂SO₄. The organic layer was concentrated and the residue was purifiedon silica with hexanes/EtOAc (1:1). The product was further purified viatriturating with (2:1) hexanes-EtOAc to provide a white solid. ¹HNMR(400 MHz, CDCl₃): 8.37 (d, J 4, 1H), 7.91 (m, 2H), 7.71 (d, J 4, 1H),7.46 (m, 3H), 6.67 (s, 1H), 4.52 (m, 1H), 4.35 (dt, 2H), 4.0 (dd, 1H),3.85 (dd, 1H), 2.58 (s, 3H), 0.79 (s, 9H), 0.11 (s, 3H), 0.07 (s, 3H).M+1: 482.

7-(tert-Butyl-dimethyl-silanyloxy)-9-(2-methanesulfonyl-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:To a suspension of urea-H₂O₂ (120 mg, 1.27 mmol) in MeCN (2.0 mL),cooled at 0° C., was added trifluroacetic anhydride (0.18 mL, 1.27 mmol)slowly. After 5 min, the cold solution was added to a solution of7-(tert-butyl-dimethyl-silanyloxy)-9-(2-methylsulfanyl-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(0.3 g, 0.62 mmol) in DCM (2.0 mL) at 0° C. The resulting mixture wasstirred at room temperature for 3 h and was quenched with NaHCO₃ (aq).The mixture was then extracted with DCM (3×) and the organic layer wasdried (Na₂SO₄) to provide a white solid after evaporation. This materialwas used directly for the next step. M+1: 498, 514.

7-(tert-Butyl-dimethyl-silanyloxy)-2-phenyl-9-[2-(1-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:A mixture of7-(tert-butyl-dimethyl-silanyloxy)-9-(2-methanesulfonyl-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one,prepared from last step (0.6 mmol) and (S)-1-phenylethylamine (1.0 mL,7.8 mmol) in dioxane (6 mL) was heated at 110° C. for 17 h. The brownsolution was cooled to room temperature and was diluted with EtOAc (10ML). The mixture was washed with H₂O (2×), dried (Na₂SO₄), andconcentrated to oil. Purification on silica (0-1% 2N NH3-MeOH in DCM)provided the product as a white solid. M+1: 555.

7-Hydroxy-2-phenyl-9-[2-(1-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one:A solution of7-(tert-butyl-dimethyl-silanyloxy)-2-phenyl-9-[2-(1-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(20 mg) in MeOH (3 mL)-DCM (1 mL) was treated with HCl (conc. 1.5 mL).After the mixture was stirred at room temperature for 16 h, it wasneutralized with NaHCO₃ (aq) and then extracted with DCM (3×). Theorganic layer was dried (Na₂SO₄) and concentrated to a solid that waspurified on silica (1-3% 2N NH₃—MeOH in DCM) to provide the product as awhite solid. ¹HNMR (400 MHz, DMSO-d₆): 8.12 (d, J 5.6,1 H), 7.94 (m,2H), 7.70 (m, 1H, NH), 7.44 (m, 3H), 7.32 (t, J 7.2, 2H), 19 (m, 1H),708 (d, J 5.6,1H), 5.50 (ds, 1H, OH), 5.01 (m, 1H, ), 4.39 (b, 1H), 4.22(bt, 1.5 H), 3.89 (d, J 4.8,1H), 3.68 (m, 0.5H), 3.3 (b, 1H), 1.45 (d, J7.2, 3H). M+1: 441.

EXAMPLE 67

8-Phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one

Step A. 4-Cyano-3-phenyl-but-3-enoic acid ethyl ester. A 250 mLround-bottom flask equipped with a large stir bar was charged with3-oxo-3-phenyl-propionic acid ethyl ester (48 g, 0.25 mol), benzene (80mL), cyanoacetic acid (23 g, 0.27 mol), ammonium acetate (4 g, 0.05mol), and acetic acid (7.5 mL, 0.13 mol) subsequently. The overallheterogeneous yellow mixture was equipped with a condenser and aDean—Stark trap and heated under reflux for 96 h. The entire mixture wascooled to room temperature and poured into a separation funnelcontaining water (100 mL). The organic layer was taken and the aqueouslayer was extracted with EtOAc (50 mL×2). Then the combined organicphases were dried over Na₂SO₄ followed by filtration and concentrationto give the crude cyanamide as a brown syrup which was purified byvacuum distillation to give the desired product as a pale yellow oil.

Step B. 8-Phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one. A 50mL round-bottom flask equipped with a stir bar was charged with thecrude cyanamide product (2.15 g, 0.01 mol), 1,3-diaminopropane (0.84 mL,0.01 mol) and 1,2-dichlorobenzene (5 mL) subsequently. The overallsolution was equipped with a air-cool condenser and heated at 160° C.overnight. The resulting solution was concentrated and the crudematerial was passed through a short path of SiO₂ column by eluted withhexanes, DCM and 1% MeOH in DCM subsequently. The fraction thatcontained product was collected and concentrated followed by washingwith EtOAc to obtain the desired pyridone product as a yellow solid.

MS m/e 227 (M+H)⁺.

EXAMPLE 68

7-Phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one.4-Cyano-3-phenyl-but-3-enoic acid ethyl ester (crude, 9.37 g, 0.043mol), ethylenediamine (3 mL, 0.043 mol) were mixed in dichlorobenze (20mL) and heated at 160° C. overnight. The resulting suspension was cooledto room temperature, filtered, and the filtrated cake was washed withEtOAc and finally dried to provide the title compound as a brownishyellow solid. MS m/e 213 (M+H)⁺.

EXAMPLE 69

1-(2-Methylsulfanyl-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one.To a mixture of 8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one(1.86 g, 8.23 mmol), sodium tert-butoxide (1.6 g, 16 mmol), BINAP (0.15g, 0.207 mmol), and Pd (OAc)₂ (55 mg, 0.2 mmol) was added toluene (20mL) and 4-chloro-2-methylthiopyrimidine (1.5 mL, 12 mmol). After purgedwith N₂ for 10 min, the overall mixture was heated at 70° C. for 3 hprior to being cooled to room temperature. The resulting material wasdiluted with saturated NHCl(aq), water, and DCM. The organic layer wastaken and the aqueous layer was extracted with DCM. The combined organiclayers were dried over Na₂SO₄, filtrated, and concentrated. Columnchromatographic purification (3% MeOH in DCM) of the crude residueafforded the title compound as a yellow solid. MS m/e 351 (M+H)⁺.

EXAMPLE 70

1-(2-Methylsulfanyl-pyrimidin-4-yl)-7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one.Following the procedure described for the synthesis of1-(2-methylsulfanyl-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one,but using 7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (1 g, 4.7mmol), sodium tert-butoxide (1.26 g, 13.16 mmol), BINAP (0.43 g, 0.7mmol), Pd (OAc)₂ (0.16 g, 0.7 mmol), toluene (20 mL) and4-chloro-2-methylthiopyrimidine (0.66 mL, 0.56 mmol). The title compoundwas isolated as a yellow solid. MS m/e 337 (M+H)⁺.

EXAMPLE 71

1-(2-Chloro-5-methyl-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one.Following the procedure described above and using8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one (0.48 g, 2.13mmol), sodium tert-butoxide (0.41 g, 4.26 mmol), BINAP (66 mg, 0.11mmol), Pd (OAc)₂ (24 mg, 0.11 mmol), toluene (5 mL) and 2,4-dichloro-5-methylpyrimidine (0.37 mL, 3.19 mmol). The title compoundwas isolated (120 mg) as a yellow solid, along with remaining startingmaterial. MS m/e 353 (M+H)⁺.

EXAMPLE 72

1-(6-Chloro-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one.To a stirred mixture of1,8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one (0.23 g, 1.0mmol), 4,6-dichloropyrmidine (0.23 g, 1.53 mmol) in DMF (3 mL) was addedexcess amount of NaH at 0° C. And the resulting slurry was stirred for1.5 h at the same temperature prior to being poured into ice andextracted with DCM (2×). The combined organic layers were washed withwater, brine, and dried over Na₂SO₄. Concentration followed by washingthe residue with isopropyl alcohol yielded the title compound as ayellow solid. MS m/e 339 (M+H)⁺.

EXAMPLE 73

1-(6-Chloro-pyrazin-2-yl)-7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one.Following the procedure described in the synthesis of1-(2-methylsulfanyl-pyrimidin-4-yl)-7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one,but using 2,6-dichloropyrimidine as the coupling component,7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (0.5 g, 2.4 mmol)was converted into the title product as a pale yellow solid. MS m/e 325(M+H)⁺.

EXAMPLE 74

1-(2-Phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one.To a solution of1-(2-methylsulfanyl-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one(1.46 g, 4.17 mmol) in DCM (10 mL) was added slowly m-CPBA (1.23 g, 70%,5.01 mmol) at 0° C. and the resulting suspension was stirred at the sametemperature for 1 h prior to being quenched with water and saturatedsodium bicarbonate. The organic layer was taken and the aqueous layerwas extracted with DCM. Then the combined organic phases were washedwith 1N NaOH, brine and dried over Na₂SO₄. Filtration followed byconcentration yielded yellow foam of desired corresponding sulfoxide,which was used directly without further purification. The crudesulfoxide (0.14 g, 0.394 mmol) and phenylethylamine (0.15 mL, 1.18 mmol)in NMP (2 mL) was heated at 100° C. for 4 h. After concentrated, thepale brown residue was diluted with isopropyl alcohol (or ethyl acetate)and the precipitate was collected as the title compound. MS m/e 424(M+H)⁺.

EXAMPLE 75

1-{2-[2-(2-Chloro-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one.Followed the same procedure described for the synthesis of1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one,the sulfoxide (0.22 g, 0.6 mmol) was displaced with2-(2-chlorophenyl)ethylamine (0.25 mL, 1.8 mmol) to give the titlecompound as a yellow solid. MS m/e 458 (M+H)⁺.

EXAMPLE 76

1-{2-[2-(2,6-Dichloro-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one.Followed the same procedure described for the synthesis of1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one,the sulfoxide (0.1 g, 0.27 mmol) was displaced with2-(2,6-dichlorophenyl)ethylamine (0.16 g, 0.82 mmol) to give the titlecompound as a yellow solid. MS m/e 492 (M+H)⁺.

EXAMPLE 77

1-{2-[2-(2,4-Dichloro-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one.Followed the same procedure in the synthesis of1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one,the sulfoxide (0.11 g, 0.3 mmol) was displaced with2-(2,4-dichlorophenyl)ethylamine (0.14 mL, 0.9 mmol) to give the titlecompound as a yellow solid. MS m/e 492 (M+H)⁺.

EXAMPLE 78

8-Phenyl-1-[2-(1S)-phenyl-ethylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one.Followed the same procedure described for the synthesis of1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one,the sulfoxide (0.12 g, 0.34 mmol) was displaced with(S)-(−)-α-methylbenzylamine (0.21 mL, 1.03 mmol) to give the titlecompound as a yellow solid. MS m/e 424 (M+H)⁺.

EXAMPLE 79

8-Phenyl-1-[2-(2S)-phenyl-propylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one.Followed the same procedure in the synthesis of1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one,the sulfoxide (0.16 g, 0.44 mmol) was displaced with(S)-(−)-β-methylbenzylamine (0.16 mL, 1.09 mmol) to give the titlecompound as a yellow solid. MS m/e 438 (M+H)⁺.

EXAMPLE 80

1-{2-[(1S)-(4-Methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one.Followed the same procedure described for the synthesis of1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one,the sulfoxide (0.34 g, 0.93 mmol) was displaced with(S)-1-(4-methoxy-phenyl)-ethylamine (0.42 g, 2.79 mmol) to give thetitle compound as a light yellow solid. MS m/e 454 (M+H)⁺.

EXAMPLE 81

1-{2-(S)-[1-(3-Bromo-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one.Followed the same procedure described for the synthesis of1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one,the sulfoxide (0.152 g, 0.42 mmol) was displaced with(S)-1-(3-bromo-phenyl)-ethylamine (0.42 g, 2.79 mmol) to give the titlecompound as a light yellow solid. MS m/e 502 (M+H)⁺.

EXAMPLE 82

8-Phenyl-1-{2-(S)-[1-(3-piperazin-1-yl-phenyl)-ethylamino]-pyrimidin-4-yl}-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one.Following the similar Pd-catalyzed amination procedure described in thesynthesis of1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one,1-{2-(S)-[1-(3-bromo-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one(0.21 g, 0.42 mmol) was reacted with piperazine (54 mg, 0.63 mmol) togive the title compound as a light yellow solid. MS m/e 508 (M+H)⁺.

EXAMPLE 83

1-{2-[2-(3-Hydroxymethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one.Following the same procedure described for the synthesis of1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one,the sulfoxide (0.29 g, 0.83 mmol) was displaced with[3-(2-amino-propyl)-phenyl]-methanol (0.3 g, 1.66 mmol) to give thetitle compound as a light yellow solid. MS m/e 468 (M+H)⁺.

EXAMPLE 84

1-{2-[2-(3-Aminomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one.To a stirred solution of1-{2-[2-(3-hydroxymethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one(0.22 g, 4.7 mmol) in THF (5 mL) was added DBU (0.14 g, 9.4 mmol) andthen diphenylphosphoryl azide (0.26 g, 9.4 mmol) and the resultingsolution was stirred at room temperature overnight. The resultingmixture was diluted with DCM and water subsequently and the separatedorganic layer was washed with saturated sodium bicarbonate and brine.Removal of the solvent provided the crude azide, which was reduced underhydrogenation conditions (H₂, Pd/C, ethanol, room temperature, 4 h).Filtration followed by concentration obtained the crude amine which waspurified with flash column chromatography (5% MeOH in DCM) to furnishthe title compound as a yellow solid. MS m/e 467 (M+H)⁺.

EXAMPLE 85

1-(6-Phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one.To a stirred mixture of1-(6-chloro-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one(0.158 mg, 0.47 mmol) and excess of K₂CO₃ in DMF (3 mL) was addedphenethylamine (0.15 mL, 1.2 mmol). The overall reaction vessel wasirradiated under microwave conditions at 150° C. for 10 min. Afterdiluted with water and EtOAc, the organic layer was taken and theaqueous layer was extracted with EtOAc. The overall organic layers werewashed with water, brine, and dried (Na₂SO₄). Filtration followed byevaporation gave the crude residue, which was washed with EtOAc/ether toprovide the title compound as a light yellow solid. MS m/e 424 (M+H)⁺.

EXAMPLE 86

1-{6-[2-(2-Chloro-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one.Followed the same procedure described for the synthesis of1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one,1-(6-chloro-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one(0.136 g, 0.40 mmol) was reacted with 2-(2-chlorophenyl)ethylamine (0.17mL, 1.2 mmol) to give the title compound as a yellow solid. MS m/e 458(M+H)⁺.

EXAMPLE 87

1-(2-Phenethylamino-pyrimidin-4-yl)-7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one.To a solution of1-(2-methylsulfanyl-pyrimidin-4-yl)-7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one(2.0 g, 5.95 mmol) in a 4:1 mixture of acetonitrile/trifluoroacetic acid(25 mL) was added urea-hydrogen peroxide (1.5 eq) followed by slowaddition of trifluroacetic anhydride (1.5 eq) at 0° C. and the resultingsuspension was stirred at the same temperature for 1 h prior to beingwarmed up to room temperature and stirred for another 2 h. At this point0.5 eq more of urea-hydrogen peroxide and trifluroacetic anhydride wereadded to consume all of remaining starting material. After concentrated,the crude material was partitioned between water and CHCl₃ and theseparated organic layer was washed with 5% NaHCO₃, brine, and thesolvent was removed to yield the mixture of sulfoxide/sulfone as anoff-white solid, which was used without any purifications.

To a stirred solution of crude sulfoxide/sulfone (0.25 g, 0.69 mmol) inNMP (5 mL) was added phenethylamine (0.1376 g) and the resulting mixturewas heated at 130° C. overnight. After cooled, the reaction mixture wasdiluted with water and DCM, the organic layer was taken and the aqueouslayer was extracted with DCM. The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure toafford the crude material, which was subjected to a preparativethin-layer chromatographic purification to provide the title compound asa pale yellow solid. MS m/e 410 (M+H)⁺.

EXAMPLE 88

1-{2-[2-(3-Hydroxymethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one.Following the same procedure described for the synthesis of1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one,the sulfoxide/sulfone (0.4 g) was displaced with[3-(2-amino-propyl)-phenyl]-methanol (1.2 eq) to give the title compoundas a light yellow solid. MS m/e 454 (M+H)⁺.

EXAMPLE 89

1-(6-Phenethylamino-pyrazin-2-yl)-7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one.To a mixture of1-(6-chloro-pyrazin-2-yl)-7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one(85 mg, 0.26 mmol), sodium tert-butoxide (70 mg, 2.8 eq), BINAP (24 mg,15% eq), and Pd (OAc)₂ (9 mg, 15% eq) was added toluene (5 mL) andphenethylamine (39 μL, 1.2 eq). After purged with N₂ for 10 min, theoverall mixture was heated at 70° C. for 3 h prior to being cooled toroom temperature. The resulting material was filtered through Celite andthe filtrated cake was washed with DCM/MeOH (98:2) and the filtrateswere concentrated. The residual material was purified by a preparativethin-layer chromatography (2% MeOH in DCM) to provide the title compoundas a pale yellow solid. MS m/e 410 (M+H)⁺.

Biological Assays

The following assays were used to characterize the ability of compoundsof the invention to inhibit the production of TNF-α and IL-1-β. Thesecond assay can be used to measure the inhibition of TNF-α and/orIL-1-β in mice after oral administration of the test compounds. Thethird assay, a glucagon binding inhibition in vitro assay, can be usedto characterize the ability of compounds of the invention to inhibitglucagon binding. The fourth assay, a cyclooxygenase enzyme (COX-1 andCOX-2) inhibition activity in vitro assay, can be used to characterizethe ability of compounds of the invention to inhibit COX-1 and/or COX-2.The fifth assay, a Raf-kinase inhibition assay, can be used tocharacterize the compounds of the invention to inhibit phosphorylationof MEK by activated Raf-kinase.

Lipopolysaccharide-Activated Monocyte TNF Production Assay

Isolation of Monocytes

Test compounds were evaluated in vitro for the ability to inhibit theproduction of TNF by monocytes activated with bacteriallipopolysaccharide (LPS). Fresh residual source leukocytes (a byproductof plateletpheresis) were obtained from a local blood bank, andperipheral blood mononuclear cells (PBMCs) were isolated by densitygradient centrifugation on Ficol-Paque Plus (Pharmacia). PBMCs weresuspended at 2×10⁶/mL in DMEM supplemented to contain 2% FCS, 10 mM, 0.3mg/mL glutamate, 100 U/mL penicillin G and 100 mg/mL streptomycinsulfate (complete media). Cells were plated into Falcon flat bottom, 96well culture plates (200 μL/well) and cultured overnight at 37° C. and6% CO₂. Non-adherent cells were removed by washing with 200 μl/well offresh medium. Wells containing adherent cells (˜70% monocytes) werereplenished with 100 μL of fresh medium.

Preparation of Test Compound Stock Solutions

Test compounds were dissolved in DMZ. Compound stock solutions wereprepared to an initial concentration of 10-50 μM. Stocks were dilutedinitially to 20-200 μM in complete media. Nine two-fold serial dilutionsof each compound were then prepared in complete medium.

Treatment of Cells with Test Compounds and Activation of TNF Productionwith Lipopolysaccharide

One hundred microliters of each test compound dilution were added tomicrotiter wells containing adherent monocytes and 100 μL completemedium. Monocytes were cultured with test compounds for 60 min at whichtime 25 μL of complete medium containing 30 ng/mL lipopolysaccharidefrom E. coli K532 were added to each well. Cells were cultured anadditional 4 hrs. Culture supernatants were then removed and TNFpresence in the supernatants was quantified using an ELISA.

TNF ELISA

Flat bottom, 96 well Corning High Binding ELISA plates were coatedovernight (4° C.) with 150 μL/well of 3 μg/mL murine anti-human TNF-αMAb (R&D Systems #MAB210). Wells were then blocked for 1 h at roomtemperature with 200 μL/well of CaCl₂-free ELISA buffer supplemented tocontain 20 mg/mL BSA (standard ELISA buffer: 20 mM, 150 mM NaCl, 2 mMCaCl₂, 0.15 mM thimerosal, pH 7.4). Plates were washed and replenishedwith 100 μL of test supernatants (diluted 1:3) or standards. Standardsconsisted of eleven 1.5-fold serial dilutions from a stock of 1 ng/mLrecombinant human TNF (R&D Systems). Plates were incubated at roomtemperature for 1 h on orbital shaker (300 rpm), washed and replenishedwith 100 μL/well of 0.5 μg/mL goat anti-human TNF-α (R&D systems#AB-210-NA) biotinylated at a 4:1 ratio. Plates were incubated for 40min, washed and replenished with 100 μL/well of alkalinephosphatase-conjugated streptavidin (Jackson ImmunoResearch#016-050-084) at 0.02 μg/mL. Plates were incubated 30 min, washed andreplenished with 200 μL/well of 1 mg/mL of p-nitrophenyl phosphate.After 30 min, plates were read at 405 nm on a V_(max) plate reader.

Data Analysis

Standard curve data were fit to a second order polynomial and unknownTNF-α concentrations determined from their OD by solving this equationfor concentration. TNF concentrations were then plotted vs. testcompound concentration using a second order polynomial. This equationwas then used to calculate the concentration of test compounds causing a50% reduction in TNF production.

Compounds of the invention can also be shown to inhibit LPS-inducedrelease of IL-1β, IL-6 and/or IL-8 from monocytes by measuringconcentrations of IL-1β, IL-6 and/or IL-8 by methods well known to thoseskilled in the art. In a similar manner to the above described assayinvolving the LPS induced release of TNF-α from monocytes, compounds ofthis invention can also be shown to inhibit LPS induced release ofIL-1β, IL-6 and/or IL-8 from monocytes by measuring concentrations ofIL-α, IL-6 and/or IL-8 by methods well known to those skilled in theart. Thus, the compounds of the invention may lower elevated levels ofTNF-α, IL-1, IL-6, and IL-8 levels. Reducing elevated levels of theseinflammatory cytokines to basal levels or below is favorable incontrolling, slowing progression, and alleviating many disease states.All of the compounds are useful in the methods of treating diseasestates in which TNF-α, IL-1β, IL-6, and IL-8 play a role to the fullextent of the definition of TNF-α-mediated diseases described herein.

Lipopolysaccharide-Activated THP1 Cell TNF Production Assay

THP1 cells are resuspended in fresh THP1 media (RPMI 1640, 10%heat-inactivated FBS, 1×PGS, 1×NEAA, plus 30 μM βME) at a concentrationof 1E6/mL. One hundred microliters of cells per well are plated in apolystyrene 96-well tissue culture. One microgram per mL of bacterialLPS is prepared in THP1 media and is transferred to the wells. Testcompounds are dissolved in 100% DMSO and are serially diluted 3 fold ina polypropylene 96-well microtiter plate (drug plate). HI control and LOcontrol wells contain only DMSO. One microliter of test compound fromthe drug plate followed by 10 μL of LPS are transferred to the cellplate. The treated cells are induced to synthesize and secrete TNF-α at37° C. for 3 h. Forty microliters of conditioned media are transferredto a 96-well polypropylene plate containing 110 μL of ECL buffer (50 mMTris-HCl pH 8.0, 100 mM NaCl, 0.05% Tween 20, 0.05% NaN₃ and 1%FBS)supplemented with 0.44 nM MAB610 monoclonal Ab (R&D Systems), 0.34 nMruthenylated AF210NA polyclonal Ab (R&D Systems) and 44 μg/mL sheepanti-mouse M280 Dynabeads (Dynal). After a 2 h incubation at roomtemperature with shaking, the reaction is read on the ECL M8 Instrument(IGEN Inc.). A low voltage is applied to the ruthenylated TNF-α immunecomplexes, which in the presence of TPA (the active component inOriglo), results in a cyclical redox reaction generating light at 620nM. The amount of secreted TNF-α in the presence of compound comparedwith that in the presence of DMSO vehicle alone (HI control) iscalculated using the formula: % control (POC)=(cpd−average LO)/(averageHI−average LO)*100. Data (consisting of POC and inhibitor concentrationin μM) is fitted to a 4-parameter equation(y=A+((B−A)/(1+((x/C){circumflex over ( )}D))), where A is the minimum y(POC) value, B is the maximum y (POC), C is the x (cpd concentration) atthe point of inflection and D is the slope factor) using aLevenburg-Marquardt non-linear regression algorithm.

The following compounds exhibit activities in the THP1 cell assay (LPSinduced TNF release) with IC₅₀ values of 20 μM or less:

-   -   1-(2-{2-[3-(1-amino-1-methyl-ethyl)-phenyl]-1-methyl-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   1-(2-{2-[4-(1-amino-ethyl)-phenyl]-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,23,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   1-(2-{2[4-(1-isopropylamino-ethyl)-phenyl]-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   1-(2-{2-[4-(2-amino-propyl)-phenyl]-1-methyl-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   1-(2-phenethylamino-pyrimidin-4-yl)-7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one;    -   1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;    -   1-(6-phenethylamino-pyrazin-2-yl)-7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one;    -   1-(6-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;    -   1-{2-(S)-[1-(3-bromo-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;    -   1-{2-[(1S)-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;    -   1-{2-[2-(2,4-dichloro-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;    -   1-{2-[2-(2,6-dichloro-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;    -   1-{2-[2-(2-chloro-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;    -   1-{2-[2-(3-aminomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;    -   1-{2-[2-(3-hydroxymethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;    -   1-{2-[2-(3-hydroxymethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one;    -   1-{2-[2-(4-aminomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   1-{6-[2-(2-chloro-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;    -   2-(2-fluorophenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   2-(2-trifluoromethylphenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   2-(3,4-dichlorophenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   2-(3,4-dimethyl-phenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   2-(3-aminophenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   2-(3-dimethylaminephenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   2-(3-ethylphenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   2-(3-nitrophenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   2-(4-fluorophenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   2-(4-methoxyphenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   2-(4-pyridyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   2-(phenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   2-(tert-butyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   2-{-[2-(3-aminomethyl-phenyl)-1-methyl-ethylamino]-pyrimidine-4-ylamino}-3-methyl-6-phenyl-3H-pyrimidin-4-one;    -   3-amino-9-{2-[2-(3-aminomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   3-amino-9-{2-[ethyl-2-(2-chlorophenyl)]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one;    -   3-amino-9-{2-[ethyl-2-phenyl]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   3-methyl-9-{2-[1-(S)-phenylethyl]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   3-nitro-9-{2-[ethyl-2-phenyl]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   7-(2-Isopropylamino-ethyl)-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   7-(ethyl-2-amino(N-benzyl))-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   7-(ethyl-2-amino)-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   7-(ethyl-2-carbamic acid benzyl        ester)-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   7-(propionic acid        )-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   7-(propionic acid ethyl        ester)-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   7-hydroxy-2-phenyl-9-[2-(1-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   8-phenyl-1-[2-(1S)-phenyl-ethylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;    -   8-phenyl-1-[2-(2S)-phenyl-propylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;    -   8-phenyl-1-{2-(S)-[1-(3-piperazin-1-yl-phenyl)-ethylamino]-pyrimidin-4-yl}-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;    -   9-(2-{2-(2-hydroxyethyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(benzyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-1(S)-isopropyl-2-ol)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-1(S)methyl-2-(3-methylaminophenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-1(S)-methyl-2-ol)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-1(S)methyl-2-phenyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-1-amido-2-phenyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-1-methyl-2-(3-aminophenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-1-methyl-2-(3-cyanophenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-1-methyl-2-(3-methylalcoholphenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-1-methyl-2-(3-methylaminophenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-2-(2-chlorophenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-2-(2-methoxyphenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-2-(3,4-dimethylphenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-2-(4-hydroxyphenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-2-(4-methoxyphenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-2-(4-methylphenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-2-aminophenyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-2-keto-2-phenyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-2-methoxy)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-2-morpholino)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-2-phenoxy)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-2-phenyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(ethyl-2-phenyl-2-ol)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(propyl-1-phenyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(propyl-2(S)-amino-3-phenyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(propyl-2,2-dimethyl-3-dimethylamino)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(-propyl-2-methyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-(propyl-3-phenyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-[3-(isopropylamino-methyl)-phenyl]-1-methyl-ethylamino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-(2-{2-amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    -   9-{2-[2-(3-aminomethyl-phenyl)-1(R)-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;        and    -   9-{2-[2-(3-aminomethyl-phenyl)-1(S)-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one.        Inhibition of LPS-Induced TNF-α Production in Mice

Male DBA/1LACJ mice are dosed with vehicle or test compounds in avehicle (the vehicle consisting of 0.5% tragacanth in 0.03 N HCl) 30minutes prior to lipopolysaccharide (2 mg/Kg, I.V.) injection. Ninetyminutes after LPS injection, blood is collected and the serum isanalyzed by ELISA for TNF-α levels.

Compounds of the invention may be shown to have anti-inflammatoryproperties in animal models of inflammation, including carageenan pawedema, collagen induced arthritis and adjuvant arthritis, such as thecarageenan paw edema model (C. A. Winter et al Proc. Soc. Exp. Biol.Med. (1962) vol 111, p 544; K. F. Swingle, in R. A. Scherrer and M. W.Whitehouse, Eds., Anti-inflammatory Agents, Chemistry and Phamacology,Vol. 13-II, Academic, New York, 1974, p. 33) and collagen inducedarthritis (D. E. Trentham et al J. Exp. Med. (1977) vol. 146, p 857; J.S. Courtenay, Nature (New Biol.) (1980), Vol 283, p 666).

¹²⁵I-Glucagon Binding Screen with CHO/hGLUR Cells

The assay is described in WO 97/16442, which is incorporated herein byreference in its entirety.

Reagents

The reagents can be prepared as follows: (a) prepare fresh 1Mo-Phenanthroline (Aldrich) (198.2 mg/mL ethanol); (b) prepare fresh 0.5MDTT (Sigma); (c) Protease Inhibitor Mix (1000×): 5 mg leupeptin, 10 mgbenzamidine, 40 mg bacitracin and 5 mg soybean trypsin inhibitor per mLDMSO and store aliquots at −20° C.; (d) 250 μM human glucagon(Peninsula): solubilize 0.5 mg vial in 575 μl 0.1N acetic acid (1 μLyields 1 μM final concentration in assay for non-specific binding) andstore in aliquots at −20° C.; (e) Assay Buffer: 20 mM Tris (pH 7.8), 1mM DTT and 3 mM o-phenanthroline; (f) Assay Buffer with 0.1% BSA (fordilution of label only; 0.01% final in assay): 10 μL 10% BSA(heat-inactivated) and 990 μL Assay Buffer; (g) ¹²⁵I-Glucagon (NEN,receptor-grade, 2200 Ci/mmol): dilute to 50,000 cpm/25 μL in assaybuffer with BSA (about 50 pM final concentration in assay).

Harvesting of CHO/hGLUR Cells for Assay

1. Remove media from confluent flask then rinse once each with PBS (Ca,Mg-free) and Enzyme-free Dissociation Fluid (Specialty Media, Inc.).

2. Add 10 mL Enzyme-free Dissoc. Fluid and hold for about 4 min at 37°C.

3. Gently tap cells free, triturate, take aliquot for counting andcentrifuge remainder for 5 min at 1000 rpm.

4. Resuspend pellet in Assay Buffer at 75000 cells per 100 μL.

Membrane preparations of CHO/hGLUR cells can be used in place of wholecells at the same assay volume. Final protein concentration of amembrane preparation is determined on a per batch basis.

Assay

The determination of inhibition of glucagon binding can be carried outby measuring the reduction of I¹²⁵-glucagon binding in the presence ofcompounds of Formula I. The reagents are combined as follows: CHO/Compound/ 250 μM hGLUR Vehicle Glucagon ¹²⁵I-Glucagon Cells TotalBinding + —/5 μl — 25 μL 100 μL Compound 5 μl/— — 25 μL 100 μLNonspecific —/5 μl 1 μl 25 μL 100 μL Binding

The mixture is incubated for 60 min at 22° C. on a shaker at 275 rpm.The mixture is filtered over pre-soaked (0.5% polyethylimine (PEI)) GF/Cfiltermat using an Innotech Harvester or Tomtec Harvester with fourwashes of ice-cold 20 mM Tris buffer (pH 7.8). The radioactivity in thefilters is determined by a gamma-scintillation counter.

Thus, compounds of the invention may also be shown to inhibit thebinding of glucagon to glucagon receptors.

Cyclooxygenase Enzyme Activity Assay

The human monocytic leukemia cell line, THP-1, differentiated byexposure to phorbol esters expresses only COX-1; the human osteosarcomacell line 143B expresses predominantly COX-2. THP-1 cells are routinelycultured in RPMI complete media supplemented with 10% FBS and humanosteosarcoma cells (HOSC) are cultured in minimal essential mediasupplemented with 10% fetal bovine serum (MEM-10%FBS); all cellincubations are at 37° C. in a humidified environment containing 5% CO₂.COX-1 Assay

In preparation for the COX-1 assay, THP-1 cells are grown to confluency,split 1:3 into RPMI containing 2% FBS and 10 mM phorbol 12-myristate13-acetate (TPA), and incubated for 48 h on a shaker to preventattachment. Cells are pelleted and resuspended in Hank's Buffered Saline(HBS) at a concentration of 2.5×10⁶ cells/mL and plated in 96-wellculture plates at a density of 5×10⁵ cells/mL. Test compounds arediluted in HBS and added to the desired final concentration and thecells are incubated for an additional 4 hours. Arachidonic acid is addedto a final concentration of 30 mM, the cells incubated for 20 minutes at37° C., and enzyme activity determined as described below.

COX-2 Assay

For the COX-2 assay, subconfluent HOSC are trypsinized and resuspendedat 3×10⁶ cells/mL in MEM-FBS containing 1 ng human IL-1b/mL, plated in96-well tissue culture plates at a density of 3×10⁴ cells per well,incubated on a shaker for 1 hour to evenly distribute cells, followed byan additional 2 hour static incubation to allow attachment. The media isthen replaced with MEM containing 2% FBS (MEM-2%FBS) and 1 ng humanEL-1b/mL, and the cells incubated for 18-22 hours. Following replacementof media with 190 mL MEM, 10 mL of test compound diluted in HBS is addedto achieve the desired concentration and the cells incubated for 4hours. The supernatants are removed and replaced with MEM containing 30mM arachidonic acid, the cells incubated for 20 minutes at 37° C., andenzyme activity determined as described below.

COX Activity Determined

After incubation with arachidonic acid, the reactions are stopped by theaddition of 1N HCl, followed by neutralization with 1N NaOH andcentrifugation to pellet cell debris. Cyclooxygenase enzyme activity inboth HOSC and THP-1 cell supernatants is determined by measuring theconcentration of PGE₂ using a commercially available ELISA (Neogen#404110). A standard curve of PGE₂ is used for calibration, andcommercially available COX-1 and COX-2 inhibitors are included asstandard controls.

Raf Kinase Assay

In vitro Raf kinase activity is measured by the extent ofphosphorylation of the substrate MEK (Map kinase/ERK kinase) byactivated Raf kinase, as described in GB 1,238,959 (incorporated hereinby reference in its entirety). Phosphorylated MEK is trapped on a filterand incorporation of radiolabeled phosphate is quantified byscintillation counting.

Materials:

Activated Raf is produced by triple transfection of Sf9 cells withbaculoviruses expressing “Glu-Glu”-epitope tagged Raf,val¹²-H-Ras, andLck. The “Glu-Glu”-epitope, Glu-Try-Met-Pro-Met-Glu, was fused to thecarboxy-terminus of full length c-Raf.

Catalytically inactive MEK (K97A mutation) is produced in Sf9 cellstransfected with a baculovirus expressing c-terminus “Glu-Glu”epitope-tagged K97A MEK1.

Anti “Glu-Glu” antibody was purified from cells grown as described in:Grussenmeyer, et al., Proceedings of the National Academy of Science,U.S.A. pp 7952-7954, 1985.

Column buffer: 20 mM Tris pH 8, 100 mM NaCl, 1 mM EDTA, 2.5 mM EGTA, 10mM MgCl₂, 2 mM DTT, 0.4 mM AEBSF, 0.1% n-octylglucopyranoside, 1 nMokadeic acid, and 10 μg/mL each of benzamidine, leupeptin, pepstatin,and aprotinin.

5× Reaction buffer: 125 mM HEPES pH=8, 25 mM MgCl₂, 5 mM EDTA, 5 mMNa₃VO₄, 100 μg/mL BSA.

Enzyme dilution buffer: 25 mM HEPES pH 8, 1 mM EDTA, 1 mM Na₃VO₄, 400μg/mL BSA.

Stop solution: 100 mM EDTA, 80 mM sodium pyrophosphate.

Filter plates: Milipore multiscreen #SE3MO78E3, Immobilon-P (PVDF).

Methods:

Protein purification: Sf9 cells were infected with baculovirus and grownas described in Williams, et al., Proceedings of the National Academy ofScience, U.S.A. pp 2922-2926, 1992. All subsequent steps were preformedon ice or at 4° C. Cells were pelleted and lysed by sonication in columnbuffer. Lysates were spun at 17,000×g for 20 min, followed by 0.22 μmfiltration. Epitope tagged proteins were purified by chromatography overGammaBind Plus affinity column to which the “Glu-Glu” antibody wascoupled. Proteins were loaded on the column followed by sequentialwashes with two column volumes of column buffer, and eluted with 50μg/mL Glu-Tyr-Met-Pro-Met-Glu in column buffer.

Raf kinase assay: Test compounds were evaluated using ten 3-fold serialdilutions starting at 10-100 μM. 10 μL of the test inhibitor or control,dissolved in 10% DMSO, was added to the assay plate followed by theaddition of 30 μL of the a mixture containing 10 μL 5× reaction buffer,1 mM ³³P-γ-ATP (20 μCi/mL), 0.5 μL MEK (2.5 mg/mL), 1 μL 50 mMβ-mercaptoethanol. The reaction was started by the addition of 10 μL ofenzyme dilution buffer containing 1 mM DTT and an amount of activatedRaf that produces linear kinetics over the reaction time course. Thereaction was mixed and incubated at room temperature for 90 min andstopped by the addition of 50 μL stop solution. 90 μL aliquots of thisstopped solution were transferred onto GFP-30 cellulose microtiterfilter plates (Polyfiltronics), the filter plates washed in four wellvolumes of 5% phosphoric acid, allowed to dry, and then replenished with25 μL scintillation cocktail. The plates were counted for ³³P gammaemission using a TopCount Scintillation Reader.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are given at the same time or differenttimes, or the therapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

For the treatment of TNF-α, IL-1β, IL-6, and IL-8 mediated diseases,cancer, and/or hyperglycemia, the compounds of the present invention maybe administered orally, parentally, by inhalation spray, rectally, ortopically in dosage unit formulations containing conventionalpharmaceutically acceptable carriers, adjuvants, and vehicles. The termparenteral as used herein includes, subcutaneous, intravenous,intramuscular, intrasternal, infusion techniques or intraperitoneally.

Treatment of diseases and disorders herein is intended to also includethe prophylactic administration of a compound of the invention, apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) believed to be in need of preventative treatment, such as, forexample, pain, inflammation and the like.

The dosage regimen for treating a TNF-α, IL-1, IL-6, and IL-8 mediateddiseases, cancer, and/or hyperglycemia with the compounds of thisinvention and/or compositions of this invention is based on a variety offactors, including the type of disease, the age, weight, sex, medicalcondition of the patient, the severity of the condition, the route ofadministration, and the particular compound employed. Thus, the dosageregimen may vary widely, but can be determined routinely using standardmethods. Dosage levels of the order from about 0.01 mg to 30 mg perkilogram of body weight per day, preferably from about 0.1 mg to 10mg/kg, more preferably from about 0.25 mg to 1 mg/kg are useful for allmethods of use disclosed herein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals.

For oral administration, the pharmaceutical composition may be in theform of, for example, a capsule, a tablet, a suspension, or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a given amount of the active ingredient. For example,these may contain an amount of active ingredient from about 1 to 2000mg, preferably from about 1 to 500 mg, more preferably from about 5 to150 mg. A suitable daily dose for a human or other mammal may varywidely depending on the condition of the patient and other factors, but,once again, can be determined using routine methods.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg,and more preferably from about 0.25 mg to 1 mg/kg.

Injectable preparations, such as sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known areusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

A suitable topical dose of active ingredient of a compound of theinvention is 0.1 mg to 150 mg administered one to four, preferably oneor two times daily. For topical administration, the active ingredientmay comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight ofthe formulation, although it may comprise as much as 10% w/w, butpreferably not more than 5% w/w, and more preferably from 0.1% to 1% ofthe formulation.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., limments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose.

For administration, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate for the indicated routeof administration. The compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, stearic acid, talc,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulphuric acids, acacia, gelatin, sodium alginate,polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted orencapsulated for conventional administration. Alternatively, thecompounds of this invention may be dissolved in saline, water,polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil,cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.Other adjuvants and modes of administration are well known in thepharmaceutical art. The carrier or diluent may include time delaymaterial, such as glyceryl monostearate or glyceryl distearate alone orwith a wax, or other materials well known in the art.

The pharmaceutical compositions may be made up in a solid form(including granules, powders or suppositories) or in a liquid form(e.g., solutions, suspensions, or emulsions). The pharmaceuticalcompositions may be subjected to conventional pharmaceutical operationssuch as sterilization and/or may contain conventional adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers, buffers etc.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting, sweetening,flavoring, and perfuming agents.

1. A compound of the formula

or a pharmaceutically acceptable salt or hydrate thereof, wherein J is═O, ═S, ═CHNO₂, ═N—CN, ═CHSO₂R^(b), ═NSO₂R^(b) or ═NHR^(b); X is,independently at each instance, N or CR³; R¹ is a saturated orunsaturated 5- or 6-membered, ring containing 0, 1, 2 or 3 atomsselected from N, O and S, wherein the ring is substituted by 0, 1, 2 or3 substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(b), —S(═O)₂N(R^(a))C(═O)OR^(b),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆ alkylNR^(a)R^(a) and—NR^(a)C₂₋₆alkylOR^(a); R² is C₁₋₈alkyl substituted by 0,1, 2 or 3substituents selected from C₁₋₂haloalkyl, halo, oxo, cyano, nitro,—C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a), and additionallysubstituted by 0, 1 or 2 substituents selected from R^(g), —C(═O)R^(g),—C(═O)OR^(g), —C(═O)NR^(a)R^(g), —C(═NR^(a))NR^(a)R^(g), —OR^(g),—OC(═O)R^(g), —OC(═O)NR^(a)R^(g), —OC(═O)N(R^(a))S(═O)₂R^(g),—OC₂₋₆alkylNR^(a)R^(g), —OC₂₋₆alkylOR^(g), —SR^(g), —S(═O)R^(g),—S(═O)₂R^(g), —S(═O)₂NR^(a)R^(g), —NR^(a)R^(g), —N(R^(a))C(═O)R^(g),—N(R^(a))C(═O)OR^(g), —N(R^(a))C(═O)NR^(a)R^(g), —C(═O)R^(e),—C(═O)OR^(e), —C(═O)NR^(a)R^(e), —C(═NR^(a))NR^(a)R^(e), —OR^(e),—OC(═O)R^(e), —OC(═O)NR^(a)R^(e), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkyNR^(a)R^(e), —OC₂₋₆alkylOR^(e), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(e), —NR^(a)R^(e), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(e) and —N(R^(a))C(═O)NR^(a)R^(e); R³ is selected fromH, R^(e), C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a); R⁶ isindependently at each instance H, R^(d), R^(e) or R^(g); R⁷ isindependently at each instance H, R^(d), R^(e) or R^(g); m is 2 or 3;R^(a) is independently, at each instance, H or R^(b); R^(b) isindependently, at each instance, phenyl, benzyl or C₁₋₆alkyl, thephenyl, benzyl and C₁₋₆alkyl being substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl,—NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl; R^(d) is independently ateach instance C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a); R^(e) isindependently at each instance C₁₋₆alkyl substituted by 0, 1, 2 or 3substituents independently selected from R^(d) and additionallysubstituted by 0 or 1 substituents selected from R^(g) ; and R^(g) isindependently at each instance a saturated, partially saturated orunsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected fromN, O and S, wherein the carbon atoms of the ring are substituted by 0, 1or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituentsselected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).
 2. A compoundaccording to claim 1, wherein R¹ is a saturated or unsaturated 5- or6-membered, ring containing 0, 1, 2 or 3 atoms selected from N, O and S,wherein the ring is substituted by 0, 1, 2 or 3 substituents selectedfrom C₁₋₄alkyl, C₁₋₄haloalkyl and halo.
 3. A compound according to claim1, wherein R¹ is a saturated or unsaturated 5- or 6-membered, ringcontaining 0, 1, 2 or 3 atoms selected from N, O and S, wherein the ringis substituted by 1, 2 or 3 substituents selected from C₁₋₄alkyl,C₁₋₄haloalkyl and halo.
 4. A compound according to claim 1, wherein R¹is phenyl substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₄alkyl, C₁₋₄haloalkyl and halo.
 5. A compound according to claim 1,wherein R¹ is thiophenyl, furanyl, pyrrolyl, oxazole or triazole, any ofwhich is substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₄alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); wherein R¹ is not thiazole,imidazole or pyrazole.
 6. A compound according to claim 1, wherein R¹ isa saturated or unsaturated 6-membered, ring containing 1, 2 or 3 atomsselected from N, O and S, wherein the ring is substituted by 0, 1, 2 or3 substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(b), —S(═O)₂N(R^(a))C(═O)OR^(b),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆ alkylNR^(a)R^(a) and—NR^(a)C₂₋₆alkylOR^(a);
 7. A compound according to claim 1, wherein R¹is an unsaturated 6-membered, ring containing 1, 2 or 3 N atoms, whereinthe ring is substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₄alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);
 8. A compound according toclaim 1, wherein R¹ is phenyl substituted by 0, 1, 2 or 3 substituentsselected from C₁₋₄alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);
 9. A compound according toclaim 1, wherein R¹ is phenyl substituted by 1, 2 or 3 substituentsselected from C₁₋₄alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);
 10. A compound according toclaim 1, wherein R¹ is phenyl, pyridinyl or pyrimidinyl, all of whichare substituted by 0,1 or 2 substituents selected from halo, C₁₋₃alkyland CF₃.
 11. A compound according to claim 1, wherein R¹ is phenyl,pyridinyl or pyrimidinyl.
 12. A compound according to claim 1, whereinR¹ is pyridinyl substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₄alkyl, C₁₋₄haloalkyl and halo.
 13. A compound according to claim 1,wherein R¹ is pyrimidinyl substituted by 0, 1, 2 or 3 substituentsselected from C₁₋₄alkyl, C₁₋₄haloalkyl and halo.
 14. A compoundaccording to claim 1, wherein R¹ is a saturated or unsaturated5-membered, ring containing 1 or 2 atoms selected from N, O and S,wherein the ring is substituted by 0, 1, 2 or 3 substituents selectedfrom C₁₋₄alkyl, C₁₋₄haloalkyl and halo.
 15. A compound of the formula

or a pharmaceutically acceptable salt or hydrate thereof, wherein J is═O, ═S, ═CHNO₂, ═N—CN, ═CHSO₂R^(b), ═NSO₂R^(b) or ═NHR^(b); X is,independently at each instance, N or CR³; R¹ is a saturated orunsaturated 5- or 6-membered, ring containing 0, 1, 2 or 3 atomsselected from N, O and S, wherein the ring is substituted by 0, 1, 2 or3 substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(b), —S(═O)₂N(R^(a))C(═O)OR^(b),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆ alkylNR^(a)R^(a) and—NR^(a)C₂₋₆alkylOR^(a); R² is C₂₋₈alkyl substituted by 0, 1, 2 or 3substituents selected from C₁₋₂haloalkyl, halo, oxo, cyano, nitro,—C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a), and additionallysubstituted by 0, 1 or 2 substituents selected from R^(g), —C(═O)R^(g),—C(═O)OR^(g), —C(═O)NR^(a)R^(g), —C(═NR^(a))NR^(a)R^(g), —OR^(g),—OC(═O)R^(g), —OC(═O)NR^(a)R^(g), —OC(═O)N(R^(a))S(═O)₂R^(g),—OC₂₋₆alkylNR^(a)R^(g), —OC₂₋₆alkylOR^(g), —SR^(g), —S(═O)R^(g),—S(═O)₂R^(g), —S(═O)₂NR^(a)R^(g), —NR^(a)R^(g), —N(R^(a))C(═O)R^(g),—N(R^(a))C(═O)OR^(g), —N(R^(a))C(═O)NR^(a)R^(g), —C(═O)R^(e),—C(═O)OR^(e), —C(═O)NR^(a)R^(e), —C(═NR^(a))NR^(a)R^(e), —OR^(e),—OC(═O)R^(e), —OC(═O)NR^(a)R^(e), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkyNR^(a)R^(e), —OC₂₋₆alkylOR^(e), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(e), —NR^(a)R^(e), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(e) and —N(R^(a))C(═O)NR^(a)R^(e); R³ is independently,in each instance, selected from H, R^(e), C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(b), —S(═O)₂N(R^(a))C(═O)OR^(b),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) or—NR^(a)C₂₋₆alkylOR^(a); R⁴ is H, R^(e), or R^(g); R⁵ is H, R^(e), orR^(g); R⁶ is independently at each instance H, R^(d), R^(e) or R^(g); R⁷is independently at each instance H, R^(d), R^(e) or R^(g); R^(a) isindependently, at each instance, H or R^(b); R^(b) is independently, ateach instance, phenyl, benzyl or C₁₋₆alkyl, the phenyl, benzyl andC₁₋₆alkyl being substituted by 0, 1, 2 or 3 substituents selected fromhalo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl,—N(C₁₋₄alkyl)C₁₋₄alkyl; R^(d) is independently at each instanceC₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a); R^(e) isindependently at each instance C₁₋₆alkyl substituted by 0, 1, 2 or 3substituents independently selected from R^(d) and additionallysubstituted by 0 or 1 substituents selected from R^(g) ; and R^(g) isindependently at each instance a saturated, partially saturated orunsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected fromN, O and S, wherein the carbon atoms of the ring are substituted by 0,1or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituentsselected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).
 16. A compoundaccording to claim 15, wherein R¹ is a saturated or unsaturated 5- or6-membered, ring containing 0, 1, 2 or 3 atoms selected from N, O and S,wherein the ring is substituted by 0, 1, 2 or 3 substituents selectedfrom C₁₋₄alkyl, C₁₋₄haloalkyl and halo.
 17. A compound according toclaim 15, wherein R¹ is phenyl substituted by 0, 1, 2 or 3 substituentsselected from C₁₋₄alkyl, C₁₋₄haloalkyl and halo.
 18. A compoundaccording to claim 15, wherein R¹ is thiophenyl, furanyl, pyrrolyl,oxazole or triazole, any of which is substituted by 0, 1, 2 or 3substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)R^(b), —C(═O)OR^(b), 13 C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); wherein R¹ isnot thiazole, imidazole or pyrazole.
 19. A compound according to claim15, wherein R¹ is a saturated or unsaturated 6-membered, ring containing1, 2 or 3 atoms selected from N, O and S, wherein the ring issubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₄alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)OR^(b), —(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).
 20. A compoundaccording to claim 15, wherein R¹ is an unsaturated 6-membered, ringcontaining 1, 2 or 3 N atoms, wherein the ring is substituted by 0, 1, 2or 3 substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(b), —S(═O)₂N(R^(a))C(═O)OR^(b),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and—NR^(a)C₂₋₆alkylOR^(a).
 21. A compound according to claim 15, wherein R¹is phenyl substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₄alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).
 22. A compoundaccording to claim 15, wherein R¹ is phenyl substituted by 1, 2 or 3substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).
 23. A compoundaccording to claim 15, wherein R¹ is phenyl, pyridinyl or pyrimidinyl,all of which are substituted by 0,1 or 2 substituents selected fromhalo, C₁₋₃alkyl and CF₃.
 24. A compound according to claim 15, whereinR¹ is phenyl, pyridinyl or pyrimidinyl.
 25. A compound according toclaim 15, wherein R¹ is pyridinyl substituted by 0, 1, 2 or 3substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl and halo.
 26. Acompound according to claim 15, wherein R¹ is pyrimidinyl substituted by0, 1, 2 or 3 substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl andhalo.
 27. A compound according to claim 15, wherein R¹ is a saturated orunsaturated 5-membered, ring containing 1 or 2 atoms selected from N, Oand S, wherein the ring is substituted by 0, 1, 2 or 3 substituentsselected from C₁₋₄alkyl, C₁₋₄haloalkyl and halo.
 28. A compound that isselected from:1-(2-{2-[3-(1-amino-1-methyl-ethyl)-phenyl]-1-methyl-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;1-(2-{2-[4-(1-amino-ethyl)-phenyl]-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,23,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;1-(2-{2[4-(1-isopropylamino-ethyl)-phenyl]-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;1-(2-{2-[4-(2-amino-propyl)-phenyl]-1-methyl-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;1-(2-phenethylamino-pyrimidin-4-yl)-7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one;1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;1-(6-phenethylamino-pyrazin-2-yl)-7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one;1-(6-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;1-{2-(S)-[1-(3-bromo-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;1-{2-[(1S)-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;1-{2-[2-(2,4-dichloro-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;1-{2-[2-(2,6-dichloro-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;1-{2-[2-(2-chloro-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;1-{2-[2-(3-aminomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;1-{2-[2-(3-hydroxymethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;1-{2-[2-(3-hydroxymethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one;1-{2-[2-(4-aminomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;1-{6-[2-(2-chloro-phenyl)-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;2-(2-fluorophenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;2-(2-trifluoromethylphenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;2-(3,4-dichlorophenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;2-(3,4-dimethyl-phenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;2-(3-aminophenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;2-(3-dimethylaminephenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;2-(3-ethylphenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;2-(3-nitrophenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;2-(4-fluorophenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;2-(4-methoxyphenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;2-(4-pyridyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;2-(phenyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;2-(tert-butyl)-9-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;2-{-[2-(3-aminomethyl-phenyl)-1-methyl-ethylamino]-pyrimidine-4-ylamino}-3-methyl-6-phenyl-3H-pyrimidin-4-one;3-amino-9-{2-[2-(3-aminomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;3-amino-9-{2-[ethyl-2-(2-chlorophenyl)]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one;3-amino-9-{2-[ethyl-2-phenyl]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;3-methyl-9-{2-[1-(S)-phenylethyl]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;3-nitro-9-{2-[ethyl-2-phenyl]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;7-(2-Isopropylamino-ethyl)-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;7-(ethyl-2-amino(N-benzyl))-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;7-(ethyl-2-amino)-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;7-(ethyl-2-carbamic acid benzylester)-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;7-(propionic acid)-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;7-(propionic acid ethylester)-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;7-hydroxy-2-phenyl-9-[2-(1-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;8-phenyl-1-[2-(1S)-phenyl-ethylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;8-phenyl-1-[2-(2S)-phenyl-propylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;8-phenyl-1-{2-(S)-[1-(3-piperazin-1-yl-phenyl)-ethylamino]-pyrimidin-4-yl}-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one;9-(2-{2-(2-hydroxyethyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(benzyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-1(S)-isopropyl-2-ol)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-1(S)methyl-2-(3-methylaminophenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-1(S)-methyl-2-ol)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-1(S)methyl-2-phenyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-1-amido-2-phenyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-1-methyl-2-(3-aminophenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-1-methyl-2-(3-cyanophenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-1-methyl-2-(3-methylalcoholphenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-1-methyl-2-(3-methylaminophenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-2-(2-chlorophenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-2-(2-methoxyphenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-2-(3,4-dimethylphenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-2-(4-hydroxyphenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-2-(4-methoxyphenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-2-(4-methylphenyl))amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-2-aminophenyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-2-keto-2-phenyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-2-methoxy)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-2-morpholino)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-2-phenoxy)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-2-phenyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(ethyl-2-phenyl-2-ol)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(propyl-1-phenyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(propyl-2(S)-amino-3-phenyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(propyl-2,2-dimethyl-3-dimethylamino)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(-propyl-2-methyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-(propyl-3-phenyl)amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-[3-(isopropylamino-methyl)-phenyl]-1-methyl-ethylamino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-{2-amino}-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-{2-[2-(3-aminomethyl-phenyl)-1(R)-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;and9-{2-[2-(3-aminomethyl-phenyl)-1(S)-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one.29. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceutically acceptable carrier.
 30. A pharmaceuticalcomposition comprising a compound according to claim 15 and apharmaceutically acceptable carrier.
 31. A method of treatment ofinflammation comprising administering an effective amount of a compoundaccording to claim
 1. 32. A method of treatment of inflammationcomprising administering an effective amount of a compound according toclaim
 15. 33. A method of treatment of rheumatoid arthritis, Pagetsdisease, osteoporosis, multiple myeloma, uveititis, acute or chronicmyelogenous leukemia, pancreatic D cell destruction, osteoarthritis,rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease,adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease,allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis,asthma, muscle degeneration, cachexia, Reiter's syndrome, type Idiabetes, type II diabetes, bone resorption diseases, graft vs. hostreaction, Alzheimer's disease, stroke, myocardial infarction, ischemiareperfusion injury, atherosclerosis, brain trauma, multiple sclerosis,cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever,myalgias due to HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza,adenovirus, the herpes viruses or herpes zoster infection in a mammalcomprising administering an effective amount of a compound according toclaim
 1. 34. A method of treatment of the inflammatory components of:rheumatoid arthritis, Pagets disease, osteoporosis, multiple myeloma,uveititis, acute or chronic myelogenous leukemia, pancreatic β celldestruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis,inflammatory bowel disease, adult respiratory distress syndrome (ARDS),psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis,anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia,Reiter's syndrome, type I diabetes, type II diabetes, bone resorptiondiseases, graft vs. host reaction, Alzheimer's disease, stroke,myocardial infarction, ischemia reperfusion injury, atherosclerosis,brain trauma, multiple sclerosis, cerebral malaria, sepsis, septicshock, toxic shock syndrome, fever, myalgias due to HIV-1, Hw-2, HIV-3,cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses orherpes zoster infection in a mammal comprising administering aneffective amount of a compound according to claim
 15. 35. A method oflowering plasma concentrations of either or both TNF-α and IL-1comprising administering an effective amount of a compound according toclaim
 1. 36. A method of lowering plasma concentrations of either orboth IL-6 and IL-8 comprising administering an effective amount of acompound according to claim
 1. 37. A method of treatment of diabetesdisease in a mammal comprising administering an effective amount of acompound according to claim 1 to produce a glucagon antagonist effect.38. A method of treatment of a pain disorder in a mammal comprisingadministering an effective amount of a compound according to claim 1.39. A method of decreasing prostaglandins production in a mammalcomprising administering an effective amount of a compound according toclaim
 1. 40. A method of decreasing cyclooxygenase enzyme activity in amammal comprising administering an effective amount of a compoundaccording to claim 1.